ES2834549T3 - Novel compound that has BLT inhibitory activity and composition, to prevent or treat inflammatory diseases, which comprises the same as active principle - Google Patents

Novel compound that has BLT inhibitory activity and composition, to prevent or treat inflammatory diseases, which comprises the same as active principle Download PDF

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ES2834549T3
ES2834549T3 ES16830783T ES16830783T ES2834549T3 ES 2834549 T3 ES2834549 T3 ES 2834549T3 ES 16830783 T ES16830783 T ES 16830783T ES 16830783 T ES16830783 T ES 16830783T ES 2834549 T3 ES2834549 T3 ES 2834549T3
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prop
ynyl
phenyl
carbonyl
mmol
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Yongseok Choi
Jae-Hong Kim
Kyeong Lee
Hyo-Kyung Han
Jun Dong Wei
Jinsun Kwon
Ja-Il Goo
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Korea University Research and Business Foundation
Industry Academic Cooperation Foundation of Dongguk University
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Industry Academic Cooperation Foundation of Dongguk University
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Abstract

Un compuesto representado por la Fórmula 1, a continuación, o una sal farmacéuticamente aceptable del mismo: **(Ver fórmula)** En la Fórmula 1, R1 es alquilo C1 a C10, R2 es **(Ver fórmula)** Ra es **(Ver fórmula)** o hidroxi. Rb es **(Ver fórmula)** Rc es **(Ver fórmula)** Rd es hidrógeno o **(Ver fórmula)** Re es **(Ver fórmula)** y R3 es hidrógeno o flúor.A compound represented by Formula 1, below, or a pharmaceutically acceptable salt thereof: ** (See formula) ** In Formula 1, R1 is C1 to C10 alkyl, R2 is ** (See formula) ** Ra is ** (See formula) ** or hydroxy. Rb is ** (See formula) ** Rc is ** (See formula) ** Rd is hydrogen or ** (See formula) ** Re is ** (See formula) ** and R3 is hydrogen or fluorine.

Description

DESCRIPCIÓNDESCRIPTION

Compuesto novedoso que tiene actividad inhibidora de BLT y composición, para prevenir o tratar enfermedades inflamatorias, que comprende el mismo como principio activoNovel compound that has BLT inhibitory activity and composition, to prevent or treat inflammatory diseases, which comprises the same as active principle

[Campo técnico][Technical field]

La presente invención se refiere a un compuesto novedoso y a un uso del mismo y, más particularmente, a un compuesto novedoso que presenta una actividad inhibidora del receptor 2 del leucotrieno B4 (BLT2) y a una composición farmacéutica para prevenir o tratar una enfermedad inflamatoria, que incluye el compuesto novedoso como principio activo.The present invention relates to a novel compound and a use thereof and, more particularly, to a novel compound exhibiting leukotriene B4 receptor 2 (BLT2) inhibitory activity and to a pharmaceutical composition for preventing or treating an inflammatory disease, which includes the novel compound as an active ingredient.

[Antecedentes de la técnica][Background of the technique]

Una respuesta inflamatoria es uno de los sistemas inmunitarios humanos activados por diversos mecanismos de acción para defenderse de acciones físicas, sustancias químicas, infecciones bacterianas o estímulos inmunitarios, que se aplican a organismos o tejidos vivos. Sin embargo, cuando dicha respuesta inflamatoria persiste, más bien, se promueve el daño a una membrana mucosa y, por tanto, se ha observado que las enfermedades inflamatorias, incluyendo artritis reumatoide, ateroesclerosis, gastritis, asma, etc. son provocadas por el eritema, la fiebre, la hinchazón, el dolor o la disfunción. Una respuesta inflamatoria de este tipo se clasifica en inflamación aguda e inflamación crónica a medida que pasa el tiempo. La inflamación aguda es una respuesta inflamatoria que dura de varios días a varias semanas y provoca un síntoma tal como el eritema, la fiebre, el dolor o la hinchazón, mientras que la inflamación crónica es un estado inflamatorio a largo plazo durante varios años a décadas e implica un cambio histológico, tal como la fibrosis o la destrucción de tejido provocadas por la infiltración de monocitos, la proliferación de fibroblastos o capilares, o un aumento del tejido conectivo.An inflammatory response is one of the human immune systems activated by various mechanisms of action to defend against physical actions, chemical substances, bacterial infections or immune stimuli, which are applied to living organisms or tissues. However, when such an inflammatory response persists, rather, damage to a mucous membrane is promoted and, therefore, inflammatory diseases, including rheumatoid arthritis, atherosclerosis, gastritis, asthma, etc. have been observed. they are caused by erythema, fever, swelling, pain, or dysfunction. An inflammatory response of this type is classified into acute inflammation and chronic inflammation as time passes. Acute inflammation is an inflammatory response that lasts from several days to several weeks and causes a symptom such as erythema, fever, pain, or swelling, while chronic inflammation is a long-term inflammatory state for several years to decades. and involves a histological change, such as fibrosis or tissue destruction caused by infiltration of monocytes, proliferation of fibroblasts or capillaries, or an increase in connective tissue.

Específicamente, cuando se aplican estímulos inflamatorios al organismo vivo, localmente, se sintetizan y se segregan histamina, bradicinina, prostaglandinas, óxido nítrico (NO), todo tipo de citocinas proinflamatorias, etc., y provocan eritema, fiebre, dolor o hinchazón, así como vasodilatación. Particularmente, en la inflamación del cuerpo, además de los factores inmunitarios comunes, por ejemplo, citocinas, tales como interferón-Y (INF-y), factor de necrosis tumoral-a (TNF-a), interleucina-1 (IL-1) e interleucina-6 (IL-6), el óxido nítrico (NO) y la prostaglandina E2 (PGE2) son bien conocidos como los principales materiales proinflamatorios.Specifically, when inflammatory stimuli are applied to the living organism, locally, histamine, bradykinin, prostaglandins, nitric oxide (NO), all kinds of pro-inflammatory cytokines, etc., are synthesized and secreted, and cause erythema, fever, pain or swelling, thus as vasodilation. Particularly in inflammation of the body, in addition to common immune factors, for example, cytokines, such as interferon-Y (INF-y), tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1 ) and interleukin-6 (IL-6), nitric oxide (NO) and prostaglandin E2 (PGE2) are well known as the main pro-inflammatory materials.

Convencionalmente, la terminación de una respuesta inflamatoria se conoce como un fenómeno que ocurre natural y pasivamente debido a una disminución de los niveles de materiales que inician la inflamación, pero se descubrió que la terminación de la inflamación es promovida activamente por lipoxinas, resolvinas o protectinas, que fueron descubiertas por Serhan et al., como las prostaglandinas, que están implicadas en el inicio de la inflamación. Por ejemplo, se ha publicado que la Resolvina E1 es eficaz para el dolor y la RvE1 induce la terminación de la inflamación y es eficaz en el tratamiento de una enfermedad inflamatoria alérgica. Además, se ha publicado que los niveles bajos de factores que promueven activamente la terminación de dicha inflamación en una enfermedad inflamatoria crónica, es decir, la lipoxina A4 y la lipixina inducidas por la aspirina, se observan en pacientes asmáticos y ateroescleróticos.Conventionally, the termination of an inflammatory response is known as a phenomenon that occurs naturally and passively due to a decrease in the levels of materials that initiate inflammation, but it was found that the termination of inflammation is actively promoted by lipoxins, resolvins or protectins. , which were discovered by Serhan et al., as prostaglandins, which are involved in the initiation of inflammation. For example, Resolvin E1 has been reported to be effective for pain and RvE1 induces the termination of inflammation and is effective in the treatment of allergic inflammatory disease. Furthermore, low levels of factors that actively promote the termination of said inflammation in chronic inflammatory disease, ie, aspirin-induced lipoxin A4 and lipixin, have been reported to be observed in asthmatic and atherosclerotic patients.

En consecuencia, aunque se han hecho varios intentos de encontrar materiales novedosos para inducir la terminación de la inflamación y, por tanto, para tratar enfermedades asociadas a la terminación anormal de la inflamación (Solicitud de Patente Coreana No Examinada N.° 10-2015-0011875), un compuesto que se sabe que está incluido en las lipoxinas, resolvinas, etc., es metabólicamente inestable y, por tanto, se degrada rápidamente en el cuerpo debido a varios dobles enlaces en su estructura y es algo difícil de desarrollar como fármaco mediante la producción masiva de un material, por lo que tiene un gran problema de capacidad de utilización como fármaco. Por otra parte, el leucotrieno B4 (LTB4) es un grupo de mediadores lipídicos inflamatorios sintetizados a partir de ácido araquidónico (AA) a través de una vía de 5-lipooxigenasa que media la inflamación aguda y crónica. Se sabe que LTB4 proporciona un efecto biológico mediante la unión a dos tipos de receptores, tales como BLT1 y BLT2. El receptor 2 de leucotrieno B4 (BLT2), como uno entre la familia de receptores acoplados a proteína G (GPCR), es un receptor que tiene una afinidad baja por LTB4 y un mediador lipídico de ácido araquidónico (AA) inducido a través de una vía dependiente de 5-lipooxigenasa.Consequently, although several attempts have been made to find novel materials to induce the termination of inflammation and thus to treat diseases associated with abnormal termination of inflammation (Unexamined Korean Patent Application No. 10-2015- 0011875), a compound known to be included in lipoxins, resolvins, etc., is metabolically unstable and therefore rapidly degrades in the body due to various double bonds in its structure and is somewhat difficult to develop as a drug by mass production of a material, so it has a big usability problem as a drug. On the other hand, leukotriene B4 (LTB4) is a group of inflammatory lipid mediators synthesized from arachidonic acid (AA) through a 5-lipoxygenase pathway that mediates acute and chronic inflammation. LTB4 is known to provide a biological effect by binding to two types of receptors, such as BLT1 and BLT2. Leukotriene B4 receptor 2 (BLT2), as one of the family of G protein-coupled receptors (GPCRs), is a receptor that has a low affinity for LTB4 and an arachidonic acid (AA) lipid mediator induced through a 5-lipoxygenase-dependent pathway.

En consecuencia, para resolver los problemas convencionales mencionados anteriormente, los inventores prepararon un compuesto novedoso que presentaba actividad inhibidora de BLT2, mientras realizaban una investigación para desarrollar un material para inducir la terminación eficaz de la inflamación, e inventaron en primer lugar un agente terapéutico para una enfermedad inflamatoria, que incluye el compuesto mencionado anteriormente. El documento WO 2008/073929 desvela el compuesto con actividad inhibidora de BLT2.Consequently, to solve the above-mentioned conventional problems, the inventors prepared a novel compound exhibiting BLT2 inhibitory activity, while conducting research to develop a material to induce effective termination of inflammation, and first invented a therapeutic agent for an inflammatory disease, which includes the above-mentioned compound. WO 2008/073929 discloses the compound with BLT2 inhibitory activity.

[Divulgación][Divulgation]

[Problema técnico] [Technical problem]

La presente invención se proporciona para resolver los problemas mencionados anteriormente y los inventores confirmaron un efecto terapéutico de un compuesto novedoso que presenta una actividad inhibidora de BLT2 sobre una enfermedad inflamatoria y, basándose en esto, se completó la presente invención.The present invention is provided to solve the above-mentioned problems, and the inventors confirmed a therapeutic effect of a novel compound exhibiting BLT2 inhibitory activity on inflammatory disease, and on the basis of this, the present invention was completed.

Por tanto, un objeto de la presente invención es proporcionar un compuesto novedoso que presente una actividad inhibidora de BLT2 o una sal farmacéuticamente aceptable del mismo.Therefore, an object of the present invention is to provide a novel compound that exhibits an inhibitory activity for BLT2 or a pharmaceutically acceptable salt thereof.

Otro objeto de la presente invención es proporcionar una composición farmacéutica para prevenir o tratar una enfermedad inflamatoria, que incluya el compuesto novedoso o una sal farmacéuticamente aceptable del mismo como principio activo.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating an inflammatory disease, which includes the novel compound or a pharmaceutically acceptable salt thereof as an active principle.

Sin embargo, los problemas técnicos que han de resolverse en la presente invención no se limitan a los problemas descritos anteriormente y los expertos habituales en la materia comprenderán con todo detalle, a partir de la siguiente descripción, otros problemas que no se describen en el presente documento.However, the technical problems to be solved in the present invention are not limited to the problems described above, and those of ordinary skill in the art will understand in full detail, from the following description, other problems that are not described herein. document.

[Solución técnica][Technical solution]

Para conseguir estos objetos de la presente invención, la presente invención proporciona un compuesto novedoso que presenta una actividad inhibidora de BLT2 o una sal farmacéuticamente aceptable del mismo.To achieve these objects of the present invention, the present invention provides a novel compound exhibiting an inhibitory activity for BLT2 or a pharmaceutically acceptable salt thereof.

De acuerdo con una realización de ejemplo de la presente invención, el compuesto puede seleccionarse del grupo que consiste en 4-(4-(3-(A/-fen¡lpentanoamido)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-butilo; N-fenil-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-etilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(2-hidroxietil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(ciclopropilmetil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-ciclohexilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(ciclohexilmetil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-isobutilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-fenil-N-(3-(4-(4-(prop-2-inil)piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(4-cianopiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(3-fluorofenil)-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-fluorofenil)-N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; 4-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(4-fluorofenil)-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(4-fluorofenil)-N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(morfolin-4-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-fenil-N-(3-(4-(piperidin-1-carbonil)fenil)prop-2-inil)pentanoamida; N,N-dietil-4-(3-(N-fenilpentanoamido)prop-1-inil)benzamida; N-fenil-N-(3-(3-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(3-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(3-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(3-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(4-fluorofenil)-N-(3-(3-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(4-fluorofenil)-N-(3-(3-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-hidroxifenil)prop-2-inil)-N-fenilpentanoamida; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-inil)fenoxi)acético; 4-(5-(3-((N-fenilpentanoamido)prop-1-in-1-il)picolinoil)piperazin-1-carboxilato de ferc-butilo; N-fenil-N-(3-(6-(piperazin-1-carbonil)piridin-3-il)prop-2-in-1-il)pentanoamida; N-(3-(6-isopropilpiperazin-1-carbonil)piridin-3-il)prop-2-in-1-il)pentanoamida; N,N-dietil-4-(3-(N-(3-fluorofenil)pentamido)prop-1-in-1-il)benzamida; N,N-dietil-4-(3-(N-(4-fluorofenil)pentamido)prop-1-in-1-il)benzamida; N-(3-(4-(N,N-dietilsulfamoil)fenil)prop-2-inil)-N-fenilpentamida; N-(3-(4-(N-isopropilsulfamoil)fenil)prop-2-inil)-N-fenilpentamida; 4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzoato de fercbutilo; ácido 4-(3-(N-fenilpentanoamido)pro-1-in-1-il)benzoico; N-etil-4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamida; N-(2-(dietilamino)etil)-4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamida; 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)acetato de etilo; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)acético; 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)propanoato de metilo; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)propiónico; ácido 2-(4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético; y ácido 2-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético.According to an exemplary embodiment of the present invention, the compound may be selected from the group consisting of 4- (4- (3- (A / -phenylpentaneamido) prop-1-¡n¡l) benzo¡l) tert-butyl piperazin-1-carboxylate; N-phenyl-N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-ethylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (2-hydroxyethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (cyclopropylmethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (cyclohexylmethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-isobutylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N-phenyl-N- (3- (4- (4- (prop-2-ynyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (4-cyanopiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Tert-Butyl 4- (4- (3- (N- (3-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (3-fluorophenyl) -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3-fluorophenyl) -N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; Tert-Butyl 4- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (4-fluorophenyl) -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (4-fluorophenyl) -N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N-phenyl-N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N, N-diethyl-4- (3- (N-phenylpentaneamido) prop-1-ynyl) benzamide; N-phenyl-N- (3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (3- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Tert-Butyl 4- (3- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (4-fluorophenyl) -N- (3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (4-fluorophenyl) -N- (3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N- phenylpentanoamide; 2- (4- (3- ( N- phenylpentanoamido) prop-1-ynyl) phenoxy) acetic acid; Tert-Butyl 4- (5- (3 - (( N- phenylpentanoamido) prop-1-in-1-yl) picolinoyl) piperazine-1-carboxylate; N-phenyl-N- (3- (6- (piperazin -1-carbonyl) pyridin-3-yl) prop-2-in-1-yl) pentanoamide; N- (3- (6-isopropylpiperazine-1-carbonyl) pyridin-3-yl) prop-2-in-1 -il) pentanoamide; N, N-diethyl-4- (3- (N- (3-fluorophenyl) pentamido) prop-1-yn-1-yl) benzamide; N, N-diethyl-4- (3- (N- (4-fluorophenyl) pentamido) prop-1-yn-1-yl) benzamide; N- (3- (4- (N, N-diethylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentamide; N- (3- (4- (N-isopropylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentamide; Fercbutyl 4- (3- (N-phenylpentanoamido) prop-1-in-1-yl) benzoate; 4- (3- (N-phenylpentanoamido) pro-1-yn-1-yl) benzoic acid; N-ethyl-4- (3- (N-phenylpentaneamido) prop-1-yn-1-yl) benzamide; N- (2- (diethylamino) ethyl) -4- (3- (N-phenylpentaneamido) prop-1-yn-1-yl) benzamide; Ethyl 2- (4- (3- (N-phenylpentanoamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- (N-phenylpentanoamido) prop-1-yn-1-yl) benzamido) acetic acid; Methyl 2- (4- (3- (N-phenylpentanoamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3- (N-phenylpentanoamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- (N- (3-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid; and 2- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid.

La presente invención proporciona una composición farmacéutica para prevenir o tratar una enfermedad inflamatoria, que incluye el compuesto novedoso o una sal farmacéuticamente aceptable del mismo como principio activo.The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, which includes the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

De acuerdo con una realización de ejemplo de la presente invención, la enfermedad inflamatoria puede seleccionarse del grupo que consiste en asma, ateroesclerosis, cáncer, prurito, artritis reumatoide y enteropatía inflamatoria.In accordance with an exemplary embodiment of the present invention, the inflammatory disease can be selected from the group consisting of asthma, atherosclerosis, cancer, pruritus, rheumatoid arthritis, and inflammatory enteropathy.

De acuerdo con otra realización de ejemplo de la presente invención, la composición puede inhibir la actividad de La presente invención proporciona un método para tratar una enfermedad inflamatoria, que incluye administrar la composición farmacéutica a un sujeto.In accordance with another exemplary embodiment of the present invention, the composition may inhibit the activity of The present invention provides a method of treating an inflammatory disease, which includes administering the pharmaceutical composition to a subject.

La presente invención proporciona un uso de la composición que incluye el compuesto novedoso o una sal farmacéuticamente aceptable del mismo para tratar una enfermedad inflamatoria.The present invention provides a use of the composition that includes the novel compound or a pharmaceutically acceptable salt thereof for treating an inflammatory disease.

[Efectos ventajosos][Advantageous effects]

La presente invención se refiere a un compuesto novedoso que presenta actividad inhibidora de BLT2 y una composición farmacéutica para prevenir o tratar una enfermedad inflamatoria, que incluye el compuesto. Los inventores identificaron un compuesto novedoso que presentaba una actividad inhibidora de BTL2 para resolver los problemas de un material convencional para tratar una enfermedad inflamatoria, por ejemplo, inestabilidad en el organismo vivo y dificultad de producción en masa, y se confirmó experimentalmente que el compuesto tiene efectos excelentes de mejora de la muerte de células cancerosas e inhibición de la metástasis de células cancerosas, un efecto inhibidor de la motilidad quimiotáctica y un efecto antiasmático y, por tanto, se espera que el compuesto se utilice eficazmente como composición farmacéutica para tratar una enfermedad inflamatoria.The present invention relates to a novel compound exhibiting BLT2 inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease, which includes the compound. The inventors identified a novel compound exhibiting BTL2 inhibitory activity to solve the problems of a conventional material for treating inflammatory disease, for example, instability in living organism and difficulty of mass production, and it was confirmed experimentally that the compound has excellent effects of enhancing cancer cell death and inhibiting cancer cell metastasis, chemotactic motility inhibiting effect and anti-asthmatic effect, and therefore the compound is expected to be used effectively as a pharmaceutical composition to treat a disease inflammatory.

[Descripción de los dibujos][Description of the drawings]

Las FIG. 1A a 1E muestran los resultados de confirmar un efecto inhibidor del crecimiento en células que expresan BLT2 (células CHO-BLT2) provocado mediante el tratamiento con un compuesto de la presente invención.FIGS. 1A to 1E show the results of confirming a growth inhibitory effect on BLT2-expressing cells (CHO-BLT2 cells) elicited by treatment with a compound of the present invention.

Las FIG. 2A y 2B muestran los resultados de confirmar un efecto de inhibición de la motilidad quimiotáctica celular y la concentración de inhibición del 50 % (CI50) en células que expresan BLT2 (células CHO-BLT2) mediante el tratamiento con un compuesto de la presente invención.FIGS. 2A and 2B show the results of confirming an inhibiting effect on cell chemotactic motility and 50% inhibiting concentration (IC50) in cells expressing BLT2 (CHO-BLT2 cells) by treatment with a compound of the present invention.

Las FIG. 3A y 3B muestran los resultados de confirmar un efecto de inhibición de la motilidad quimiotáctica celular en células que expresan BLT2 (células CHO-BLT2) o en células que expresan BLT1 (células CHO-BLT1) mediante el tratamiento con un compuesto de la presente invención.FIGS. 3A and 3B show the results of confirming an inhibiting effect on cell chemotactic motility in cells expressing BLT2 (CHO-BLT2 cells) or in cells expressing BLT1 (CHO-BLT1 cells) by treatment with a compound of the present invention. .

Las FIG. 4A y 4B muestran los resultados de confirmar los efectos inhibidores de la unión a LTB4 y BLT2 en células que expresan BLT2 (células CHO-BLT2) mediante el tratamiento con un compuesto de la presente invención.FIGS. 4A and 4B show the results of confirming the inhibitory effects of LTB4 and BLT2 binding in BLT2-expressing cells (CHO-BLT2 cells) by treatment with a compound of the present invention.

Las FIG. 5A y 5B muestran los resultados de confirmar un efecto de inhibición de la generación de especies reactivas de oxígeno en células MDA-MB-231 o MDA-MB-435 mediante el tratamiento con un compuesto de la presente invención.FIGS. 5A and 5B show the results of confirming an inhibiting effect of the generation of reactive oxygen species in MDA-MB-231 or MDA-MB-435 cells by treatment with a compound of the present invention.

Las FIG. 6A y 6B muestran los resultados de confirmar un efecto de inhibición de los niveles de expresión de interleucina-8 (IL-8) en células MDA-MB-231 o MDA-MB-435 mediante el tratamiento con un compuesto de la presente invención.FIGS. 6A and 6B show the results of confirming an effect of inhibition of interleukin-8 (IL-8) expression levels in MDA-MB-231 or MDA-MB-435 cells by treatment with a compound of the present invention.

Las FIG. 7A y 7B muestran los resultados de confirmar un efecto de inhibición de la invasión de células cancerosas en células MDA-MB-231 o células MDA-MB-435 mediante el tratamiento con un compuesto de la presente invención.FIGS. 7A and 7B show the results of confirming a cancer cell invasion inhibition effect on MDA-MB-231 cells or MDA-MB-435 cells by treatment with a compound of the present invention.

Las FIG. 8, 9A y 9B muestran los resultados de confirmar un efecto de inhibición de la metástasis de células cancerosas mediante el tratamiento con un compuesto de la presente invención.FIGS. 8, 9A and 9B show the results of confirming an effect of inhibiting cancer cell metastasis by treatment with a compound of the present invention.

La FIG. 10 muestra los resultados de confirmar un efecto de reducción de la hipersensibilidad de las vías respiratorias (HSVR) en ratones con asma grave inducida mediante el tratamiento con un compuesto de la presente invención.FIG. 10 shows the results of confirming an effect of reducing airway hypersensitivity (HSVR) in mice with severe asthma induced by treatment with a compound of the present invention.

La FIG. 11 muestra los resultados de confirmar un efecto de reducción de la generación de interleucina-4 (IL-4) en ratones con asma grave inducida mediante el tratamiento con un compuesto de la presente invención.FIG. 11 shows the results of confirming an effect of reducing the generation of interleukin-4 (IL-4) in mice with severe asthma induced by treatment with a compound of the present invention.

La FIG. 12 muestra los resultados de confirmar un efecto de reducción de la hipersensibilidad de las vías respiratorias (HSVR) en ratones con asma grave inducida mediante el tratamiento con un compuesto de la presente invención.FIG. 12 shows the results of confirming an effect of reducing airway hypersensitivity (HSVR) in mice with severe asthma induced by treatment with a compound of the present invention.

Las FIG. 13A a 13C muestran los resultados de confirmar que el influjo de células y neutrófilos totales en la cavidad abdominal de un ratón se reduce en ratones con asma grave inducida mediante el tratamiento con un compuesto de la presente invención.FIGS. 13A to 13C show the results of confirming that the influx of cells and total neutrophils into the abdominal cavity of a mouse is reduced in mice with severe asthma induced by treatment with a compound of the present invention.

Las FIG. 14A y 14B muestran los resultados de confirmar que el influjo de células y neutrófilos totales en la cavidad abdominal de un ratón en ratones con asma inducida se reduce mediante el tratamiento con un compuesto de la presente invención.FIGS. 14A and 14B show the results of confirming that the influx of cells and total neutrophils into the abdominal cavity of a mouse in mice with induced asthma is reduced by treatment with a compound of the present invention.

[Modos de la invención][Modes of the invention]

Los inventores identificaron específicamente los efectos de mejora de la muerte de células cancerosas, la inhibición de la metástasis de células cancerosas y la inhibición de la motilidad quimiotáctica dependiente de BLT2, y un efecto antiasmático basado en el hecho de que el crecimiento de células que expresan BLT2 puede inhibirse considerablemente cuando se trata con un compuesto novedoso preparado en un ejemplo y, por tanto, se completó la presente invención.The inventors specifically identified the effects of enhancing cancer cell death, inhibition of cancer cell metastasis and inhibition of BLT2-dependent chemotactic motility, and an anti-asthmatic effect based on the fact that the growth of cells expressing BLT2 can be considerably inhibited when treated with a novel compound prepared in an example, and therefore the present invention was completed.

En lo sucesivo en el presente documento, se describirá en detalle la presente invención. Hereinafter, the present invention will be described in detail.

La presente invención proporciona un compuesto representado por la Fórmula 1, a continuación, o una sal farmacéuticamente aceptable del mismo.The present invention provides a compound represented by Formula 1, below, or a pharmaceutically acceptable salt thereof.

Figure imgf000005_0001
Figure imgf000005_0001

En la Fórmula 1,In Formula 1,

R1 puede ser un alquilo C1 a C10,R1 can be a C1 to C10 alkyl,

R2 puede serR2 can be

Figure imgf000005_0002
Figure imgf000005_0002

o hidroxi, or hydroxy,

Rb puede serRb can be

Figure imgf000006_0001
Figure imgf000006_0001

Rc puede serRc can be

Figure imgf000006_0002
Figure imgf000006_0002

Rd puede ser hidrogeno oRd can be hydrogen or

Figure imgf000006_0003
Figure imgf000006_0003

Re puede serRe can be

Figure imgf000006_0004
Figure imgf000006_0004

yY

R3 puede ser hidrógeno o flúor.R3 can be hydrogen or fluorine.

Los siguientes son ejemplos de ejemplo del compuesto representado por la Fórmula 1 de acuerdo con la presente invención: 4-(4-(3-(N-fenilpentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-fenil-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-etilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(2-hidroxietil)piperazin-1-carbonil)fenil)prop-2 -inil)-N-fenilpentanoamida; N-(3-(4-(4-(ciclopropilmetil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-ciclohexilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(ciclohexilmetil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-isobutilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-fenil-N-(3-(4-(4-(prop-2-inil)piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(4-cianopiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(3-fluorofenil)-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-fluorofenil)-N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; 4-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(4-fluorofenil)-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(4-fluorofenil)-N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(morfolin-4-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-fenil-N-(3-(4-(piperidin-1-carbonil)fenil)prop-2-inil)pentanoamida; N,N-dietil-4-(3-(N-fenilpentanoamido)prop-1-inil)benzamida; N-fenil-N-(3-(3-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(3-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(3-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(3-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(4-fluorofenil)-N-(3-(3-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(4-fluorofenil)-N-(3-(3-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-hidroxifenil)prop-2-inil)-N-fenilpentanoamida; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-inil)fenoxi)acético; 4-(5-(3-(N-fenilpentanoamido)prop-1 -in-1 -il)picolinoil)piperazin-1 -carboxilato de ferc-butilo; N-fenil-N-(3-(6-(piperazin-1-carbonil)piridin-3-il)prop-2-in-1-il)pentanoamida; N-(3-(6-isopropilpiperazin-1-carbonil)piridin-3-il)prop-2-in-1-il)pentanoamida; N,N-dietil-4-(3-(N-(3-fluorofenil)pentamido)prop-1 -in-1 -il)benzamida; N,N-dietil-4-(3-(N-(4-fluorofenil)pentamido)prop-1-in-1-il)benzamida; N-(3-(4-(N,N-dietilsulfamoil)fenil)prop-2-inil)-N-fenilpentamida; N-(3-(4-(N-isopropilsulfamoil)fenil)prop-2-inil)-N-fenilpentamida; 4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzoato de ferc-butilo; ácido 4-(3-(N fenilpentanoamido)pro-1-in-1-il)benzoico; N-et¡l-4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzam¡da; N-(2-(dietilamino)etil)-4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamida; 2-(4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)acetato de et¡lo; ác¡do 2-(4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)acét¡co; 2-(4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)propanoato de met¡lo; ác¡do 2-(4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)prop¡ón¡co; ác¡do 2-(4-(3-(N-(3-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡co; y ác¡do 2-(4-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡co.The following are exemplary examples of the compound represented by Formula 1 according to the present invention: tert-butyl 4- (4- (3- (N-phenylpentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate ; N-phenyl-N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-ethylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (2-hydroxyethyl) piperazine-1-carbonyl) phenyl) prop-2 -inyl) -N-phenylpentanoamide; N- (3- (4- (4- (cyclopropylmethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (cyclohexylmethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-isobutylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N-phenyl-N- (3- (4- (4- (prop-2-ynyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (4-cyanopiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Tert-Butyl 4- (4- (3- (N- (3-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (3-fluorophenyl) -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3-fluorophenyl) -N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; Tert-Butyl 4- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (4-fluorophenyl) -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (4-fluorophenyl) -N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N-phenyl-N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N, N-diethyl-4- (3- (N-phenylpentaneamido) prop-1-ynyl) benzamide; N-phenyl-N- (3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (3- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Tert-Butyl 4- (3- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (4-fluorophenyl) -N- (3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (4-fluorophenyl) -N- (3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N-phenylpentanoamide; 2- (4- (3- (N-phenylpentanoamido) prop-1-ynyl) phenoxy) acetic acid; Tert-Butyl 4- (5- (3- (N-phenylpentanoamido) prop-1 -in-1 -yl) picolinoyl) piperazine-1-carboxylate; N-phenyl-N- (3- (6- (piperazine-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentanoamide; N- (3- (6-isopropylpiperazine-1-carbonyl) pyridin-3-yl) prop-2-yn-1-yl) pentanoamide; N, N-diethyl-4- (3- (N- (3-fluorophenyl) pentamido) prop-1 -in-1 -yl) benzamide; N, N-diethyl-4- (3- (N- (4-fluorophenyl) pentamido) prop-1-yn-1-yl) benzamide; N- (3- (4- (N, N-diethylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentamide; N- (3- (4- (N-isopropylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentamide; Tert-Butyl 4- (3- (N-phenylpentaneamido) prop-1-yn-1-yl) benzoate; acid 4- (3- (N phenylpentanoamido) pro-1-yn-1-yl) benzoic; N-ethyl-4- (3- (N-phenylpentane) prop-1-in-1-il) benzamide; N- (2- (diethylamino) ethyl) -4- (3- (N-phenylpentaneamido) prop-1-yn-1-yl) benzamide; Ethyl 2- (4- (3- (N-phenylpentane) prop-1-n-1-l) benzamide) acetate; 2- (4- (3- (N-phenylpentane) prop-1-n-1-l) benzamide) acetic acid; Methyl 2- (4- (3- (N-phenylpentanoamide) prop-1-n-1-l) benzamido) propanoate; 2- (4- (3- (N-phenylpentane) prop-1-in-1-¡l) benzamide) propionic acid; 2- (4- (3- (N- (3-fluorophenyl) pentanoamide) prop-1-inl) phenoxy) acetic acid; and 2- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-inl) phenoxy) acetic acid.

La expres¡ón "farmacéut¡camente aceptable" ut¡l¡zada en el presente documento se ref¡ere a un compuesto o compos¡c¡ón que es adecuado para usarse en contacto con el tej¡do de un sujeto (por ejemplo, un ser humano) deb¡do a una relac¡ón benef¡c¡o/r¡esgo razonable s¡n tox¡c¡dad exces¡va, ¡rr¡tac¡ón, reacc¡ones alérg¡cas, u otros problemas o compl¡cac¡ones, y se ¡ncluye dentro del ámb¡to del buen cr¡ter¡o méd¡co.The term "pharmaceutically acceptable" used herein refers to a compound or composition that is suitable for use in contact with the tissue of a subject (eg , a human being) due to a reasonable beneficial / risk relationship without excessive toxicity, irritation, allergic reactions, or other problems or complications, and is included within the purview of good medical judgment.

El térm¡no "sal" ut¡l¡zado en el presente documento es una sal de ad¡c¡ón de ác¡do formada por un ác¡do l¡bre farmacéut¡camente aceptable. La sal de ad¡c¡ón de ác¡do se obt¡ene a part¡r de ác¡dos ¡norgán¡cos, tales como ác¡do clorhídr¡co, ác¡do nítr¡co, ác¡do fosfór¡co, ác¡do sulfúr¡co, bromuro de h¡drógeno, yoduro de h¡drógeno, n¡truro y ác¡do fosfór¡co, y ác¡dos orgán¡cos no tóx¡cos, tales como mono y d¡carbox¡latos al¡fát¡cos, alcanoatos sust¡tu¡dos con fen¡lo, alcanoatos y alcand¡oatos de h¡drox¡lo, ác¡dos aromát¡cos, ác¡dos sulfón¡cos al¡fát¡cos y aromát¡cos. D¡chas sales farmacéut¡camente no tóx¡cas ¡ncluyen sulfatos, p¡rosulfatos, b¡sulfatos, sulf¡tos, b¡sulf¡tos, n¡tratos, fosfatos, monoh¡drogenofosfatos, d¡h¡drogenofosfatos, metafosfatos, p¡rofosfatocloruros, bromuros, yoduros, fluoruros, acetatos, prop¡onatos, decanoatos, capr¡latos, acr¡latos, form¡atos, ¡sobut¡ratos, capratos, heptanoatos, prop¡olatos, oxalatos, malonatos, succ¡natos, suberatos, sebacatos, fumaratos, maleatos, but¡no-1,4-d¡oatos, hexano-1,6-d¡oatos, benzoatos, clorobenzoatos, met¡lbenzoatos, d¡n¡trobenzoatos, benzoatos de h¡drox¡lo, metox¡benzoatos, ftalatos, tereftalatos, bencenosulfonatos, toluenosulfonatos, clorobencenosulfonatos, x¡lenosulfonatos, fen¡lacetatos, fen¡lprop¡onatos, fen¡lbut¡ratos, c¡tratos, lactatos, p-h¡drox¡lbut¡ratos, gl¡colatos, malatos, tartratos, metanosulfonatos, propanosulfonatos, naftaleno-1-sulfonatos, naftaleno-2-sulfonatos y mandelatos.The term "salt" used herein is an acid addition salt formed from a pharmaceutically acceptable free acid. The acid addition salt is obtained from Norwegian acids, such as hydrochloric acid, nitric acid, phosphoric acid. co, sulfuric acid, hydrogen bromide, hydrogen iodide, nitride and phosphoric acid, and non-toxic organic acids, such as mono and dicarbox Alkatic acids, phenyl substituted alkanoates, hydroxyl alkanoates and alkanoates, aromatic acids, alphasphatic sulfonic acids and aromatics. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates. , pyrophosphochlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, sobutrates, caprates, heptanoates, propylates, oxalates, malonates, succ¡ natos, suberates, sebacates, fumarates, maleates, butyno-1,4-dioates, hexane-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dintrobenzoates, hydrobenzoates drox¡lo, methoxybenzoates, phthalates, terephthalates, benzene sulphonates, toluene sulphonates, chlorobenzene sulphonates, xylene sulphonates, phenolacetates, phenlprop¡onates, phenylbutyrates, strata, lactates, ph¡droxylbut¡ rat, glycolates, malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

La sal de ad¡c¡ón de ác¡do de acuerdo con la presente ¡nvenc¡ón puede prepararse med¡ante un método convenc¡onal, por ejemplo, d¡solv¡endo compuestos representados por las Fórmulas 1 a 4 en una soluc¡ón acuosa de ác¡do en exceso y prec¡p¡tando la sal resultante usando un d¡solvente orgán¡co m¡sc¡ble con agua, por ejemplo, metanol, etanol, acetona o aceton¡tr¡lo. Además, la sal de ad¡c¡ón de ác¡do de acuerdo con la presente ¡nvenc¡ón puede prepararse evaporando un d¡solvente o un ác¡do en exceso de esta mezcla y, después, deshidratando la mezcla resultante o f¡ltrando por succ¡ón una sal prec¡p¡tada.The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving compounds represented by Formulas 1 to 4 in a aqueous solution of excess acid and capturing the resulting salt using an organic solvent more soluble with water, for example, methanol, ethanol, acetone or acetonitrile. Furthermore, the acid addition salt according to the present invention can be prepared by evaporating a solvent or an excess acid from this mixture and then dehydrating the resulting mixture of Filtering by suction a precipted salt.

Además, la sal de metal farmacéut¡camente aceptable puede prepararse usando una base. Puede obtenerse una sal de metal alcal¡no o de metal alcal¡notérreo, por ejemplo, d¡solv¡endo un compuesto en una cant¡dad en exceso de una soluc¡ón de h¡dróx¡do de metal alcal¡no o de h¡dróx¡do de metal alcal¡notérreo, f¡ltrando una sal de compuesto ¡nsoluble y deshidratando la soluc¡ón restante a través de evaporac¡ón. En este caso, una sal de sod¡o, potas¡o o calc¡o es farmacéut¡camente aprop¡ada para la sal de metal. Además, se obt¡ene una sal de plata correspondente a la sal de metal med¡ante reacc¡ón entre una sal de metal alcal¡no o metal alcal¡notérreo y una sal de plata adecuada (por ejemplo, n¡trato de plata).Furthermore, the pharmaceutically acceptable metal salt can be prepared using a base. An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess amount of an alkali metal hydroxide solution or of alkaline earth metal hydroxide, filtering a salt of the insoluble compound and dehydrating the remaining solution through evaporation. In this case, a sodium, potassium or calcium salt is pharmaceutically appropriate for the metal salt. Furthermore, a silver salt corresponding to the metal salt is obtained by reaction between an alkali metal or alkaline earth metal salt and a suitable silver salt (for example, silver nitrate). ).

En una real¡zac¡ón de ejemplo de la presente ¡nvenc¡ón, se prepararon compuestos novedosos que presentaban una act¡v¡dad ¡nh¡b¡dora de BLT2 (véanse los Ejemplos 1 a 46), y se conf¡rmó que el crec¡m¡ento de células que expresan BLT2 se ¡nh¡bía med¡ante el tratamiento con el compuesto novedoso (véase el Ejemplo Exper¡mental 2). Además, se conf¡rmó que la mot¡l¡dad qu¡m¡otáct¡ca de las células que expresan BLT2 puede ¡nh¡b¡rse (véase el Ejemplo Exper¡mental 3). Además, se conf¡rmó un efecto ¡nh¡b¡dor de la un¡ón de LTB4 y BLT2 usando el compuesto (véase el Ejemplo Exper¡mental 4), se conf¡rmaron la ¡nh¡b¡c¡ón de espec¡es react¡vas de oxígeno en células, la ¡nh¡b¡c¡ón de la expres¡ón de IL-8, la ¡nh¡b¡c¡ón de la ¡nvas¡ón de células cancerosas y la ¡nh¡b¡c¡ón de la metástas¡s de células cancerosas (véase el Ejemplo Exper¡mental 5) y tamb¡én se conf¡rmó específ¡camente que los compuestos t¡enen efectos de reducc¡ón de la h¡persens¡b¡l¡dad de las vías resp¡rator¡as (HSVA), ¡nh¡b¡c¡ón de la generac¡ón de IL-4 e ¡nh¡b¡c¡ón del ¡nflujo de células ¡nmun¡tar¡as en la cav¡dad abdom¡nal de un ratón en ratones con asma ¡nduc¡da (véase el Ejemplo Exper¡mental 6 ) y, por tanto, se conf¡rmó que los compuestos pueden usarse muy ef¡cazmente como una compos¡c¡ón farmacéut¡ca para una enfermedad ¡nflamator¡a.In an exemplary embodiment of the present invention, novel compounds exhibiting an inhibitory activity of BLT2 (see Examples 1 to 46) were prepared and confirmed It was shown that the growth of cells expressing BLT2 was inhibited by treatment with the novel compound (see Experimental Example 2). Furthermore, it was confirmed that the chemotactic motility of cells expressing BLT2 can be inhibited (see Experimental Example 3). Furthermore, a binding effect of LTB4 and BLT2 binding was confirmed using the compound (see Experimental Example 4), the binding of reactive oxygen species in cells, the expression of IL-8, the inhibition of cancer cell invasion and the Cancer cell metastasis targeting (see Experimental Example 5) and it was also specifically confirmed that the compounds have h ¡Nh¡b¡t¡on of the IL-4 generation and ¡nh¡b¡t¡on of the flow of Immune cells in the abdominal cavity of a mouse in mice with induced asthma (see Experimental Example 6) and, therefore, it was confirmed that the compounds can be used very effectively as a pharmaceutical composition for an inflammatory disease.

Por tanto, la presente ¡nvenc¡ón proporc¡ona una compos¡c¡ón farmacéut¡ca para preven¡r o tratar una enfermedad ¡nflamator¡a, que ¡ncluye el compuesto o una sal farmacéut¡camente aceptable del m¡smo.Thus, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease, which includes the compound or a pharmaceutically acceptable salt thereof.

Por otra parte, el térm¡no "prevenc¡ón" ut¡l¡zado en el presente documento se ref¡ere a todas las acc¡ones de ¡nh¡b¡c¡ón de una enfermedad ¡nflamator¡a o retraso del ¡n¡c¡o de la m¡sma med¡ante la adm¡n¡strac¡ón de la compos¡c¡ón farmacéut¡ca de acuerdo con la presente ¡nvenc¡ón.On the other hand, the term "prevention" used in the present document refers to all the actions of an inflammatory disease or delay of the The same by administering the pharmaceutical composition in accordance with the present invention.

El térm¡no "tratam¡ento" ut¡l¡zado en el presente documento se ref¡ere a todas las acc¡ones ¡mpl¡cadas en al¡v¡ar o mod¡f¡car benef¡c¡osamente los síntomas de una enfermedad ¡nflamator¡a med¡ante la adm¡n¡strac¡ón de la compos¡c¡ón farmacéut¡ca de acuerdo con la presente ¡nvenc¡ón.The term "treatment" used in this document refers to all the actions involved in alleviating or beneficially modifying the symptoms of an inflammatory disease through the administration of the pharmaceutical composition in accordance with the present invention.

En la presente ¡nvenc¡ón, la enfermedad ¡nflamator¡a es una enfermedad provocada por la sobreexpres¡ón de BLT2 y puede ser una o más seleccionadas de asma, ateroesclerosis, cáncer, prurito, artritis reumatoide y enteropatía inflamatoria, pero la presente invención no se limita a las mismas. Aparte de las enfermedades presentadas en la memoria descriptiva, se incluyen todas las enfermedades inflamatorias asociadas a BLT2 conocidas en la técnica como enfermedades inflamatorias que pueden prevenirse o tratarse con un compuesto que tenga la estructura de Fórmula 1 de la presente invención. En un ejemplo particular, el cáncer puede ser cualquier cáncer provocado por la sobreexpresión de BLT2 o Ras, que es un gen tumoral. El cáncer puede seleccionarse, pero sin limitación, del grupo que consiste en cáncer de riñón, cáncer de próstata, cáncer de páncreas, cáncer de mama, tumores cerebrales, cáncer de piel y cáncer de hígado.At the present invention, inflammatory disease is a disease caused by overexpression of BLT2 and it can be one or more selected from asthma, atherosclerosis, cancer, pruritus, rheumatoid arthritis, and inflammatory enteropathy, but the present invention is not limited thereto. Apart from the diseases presented in the specification, all BLT2-associated inflammatory diseases known in the art are included as inflammatory diseases that can be prevented or treated with a compound having the structure of Formula 1 of the present invention. In a particular example, the cancer can be any cancer caused by the overexpression of BLT2 or Ras, which is a tumor gene. Cancer can be selected, but not limited to, from the group consisting of kidney cancer, prostate cancer, pancreatic cancer, breast cancer, brain tumors, skin cancer, and liver cancer.

En la presente invención, BLT2, como uno entre la familia de receptores acoplados a proteína G (GPCR), es un receptor que tiene una afinidad baja por LTB4 y, por tanto, la composición de la presente invención inhibe el crecimiento celular provocado por b LT2 para prevenir o tratar una enfermedad inflamatoria. Más específicamente, la motilidad quimiotáctica inducida por LTB4 puede inhibirse mediante la inhibición de la generación de ROS inducida por la actividad de BLT2.In the present invention, BLT2, as one among the family of G-protein-coupled receptors (GPCR), is a receptor that has a low affinity for LTB4 and, therefore, the composition of the present invention inhibits cell growth caused by b LT2 to prevent or treat an inflammatory disease. More specifically, LTB4-induced chemotactic motility can be inhibited by inhibiting the generation of ROS induced by BLT2 activity.

El término "inhibición" utilizado en el presente documento se refiere a la inhibición de una determinada etapa entre la transcripción génica, el procesamiento de ARNm, la traducción, la translocación y la maduración, o la inhibición de la unión entre proteínas, la activación de una proteína o la transmisión de una señal a través de ella.The term "inhibition" used herein refers to the inhibition of a certain step between gene transcription, mRNA processing, translation, translocation and maturation, or inhibition of protein binding, activation of a protein or the transmission of a signal through it.

La composición farmacéutica de la presente invención puede incluir un vehículo farmacéuticamente aceptable además de un principio activo. En este caso, el vehículo farmacéuticamente aceptable se usa convencionalmente en la formulación, e incluye, pero sin limitación, lactosa, dextrosa, sacarosa, sorbitol, manitol, almidón, goma arábiga, fosfato de calcio, alginato, gelatina, silicato de calcio, celulosa microcristalina, polivinilpirrolidona, celulosa, agua, jarabe, metilcelulosa, hidroxibenzoato de metilo, hidroxibenzoato de propilo, talco, estearato de magnesio y aceite mineral. Además, aparte de los componentes, puede incluirse adicionalmente un lubricante, un agente humectante, un agente edulcorante, un agente aromatizante, un emulsionante, un agente de suspensión o un conservante.The pharmaceutical composition of the present invention can include a pharmaceutically acceptable carrier in addition to an active ingredient. In this case, the pharmaceutically acceptable carrier is conventionally used in the formulation, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, gelatin, calcium silicate, cellulose. microcrystalline, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. In addition, apart from the components, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent or a preservative may be further included.

La composición farmacéutica de la presente invención puede administrarse por vía oral o por vía parenteral (por ejemplo, por vía intravenosa, por vía subcutánea, por vía intraperitoneal o localmente), dependiendo del método deseado, y la dosis de la composición farmacéutica puede variar, dependiendo del estado y el peso corporal del paciente, la gravedad de la enfermedad, el tipo de fármaco, la vía y momento de administración, y un experto habitual en la materia puede seleccionarla adecuadamente.The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or locally), depending on the desired method, and the dosage of the pharmaceutical composition can vary, depending on the condition and body weight of the patient, the severity of the disease, the type of drug, the route and time of administration, and one of ordinary skill in the art can select it appropriately.

La composición farmacéutica de la presente invención se administra en una cantidad farmacéuticamente eficaz. La "cantidad farmacéuticamente eficaz" utilizada en el presente documento se refiere a una cantidad suficiente para tratar una enfermedad con una relación beneficio/riesgo razonable aplicable para el tratamiento médico y la dosis eficaz puede determinarse mediante parámetros que incluyen el tipo de enfermedad del paciente, la gravedad, la actividad del fármaco, la sensibilidad a un fármaco, el momento de administración, la vía de administración y la tasa de excreción, la duración del tratamiento y los fármacos utilizados simultáneamente y otros parámetros bien conocidos en el campo de la medicina. La composición farmacéutica de la presente invención puede administrarse por separado o en combinación con otros agentes terapéuticos y puede administrarse secuencial o simultáneamente con un agente terapéutico convencional o puede administrarse en una dosis única o en dosis múltiples. Teniendo en cuenta todos los parámetros mencionados anteriormente, es importante conseguir el efecto máximo con la dosis mínima sin efectos secundarios y un experto habitual en la materia puede determinar fácilmente una dosis de este tipo.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The "pharmaceutically effective amount" used herein refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and the effective dose can be determined by parameters including the type of disease of the patient, severity, drug activity, sensitivity to a drug, timing of administration, route of administration and excretion rate, duration of treatment and drugs used concurrently, and other parameters well known in the field of medicine. The pharmaceutical composition of the present invention can be administered separately or in combination with other therapeutic agents and can be administered sequentially or simultaneously with a conventional therapeutic agent or it can be administered in a single dose or in multiple doses. Taking into account all the parameters mentioned above, it is important to achieve the maximum effect with the minimum dose without side effects and one of ordinary skill in the art can easily determine such a dose.

Específicamente, la cantidad eficaz de la composición farmacéutica de la presente invención puede depender de la edad del paciente, el sexo, el estado y el peso corporal, la tasa de absorción del principio activo en el cuerpo, la tasa de inactivación, la tasa de excreción, el tipo de enfermedad o el fármaco utilizado en combinación y puede administrarse generalmente a 0,001 a 150 mg, y preferentemente de 0,01 a 100 mg por kg de peso corporal a diario o en días alternos, o puede dividirse en una o tres administraciones diarias. Sin embargo, la cantidad eficaz puede variar dependiendo de la vía de administración, la gravedad de la obesidad, el sexo, el peso corporal o la edad y, por tanto, el alcance de la presente invención no se ve limitado por la dosis de ninguna manera.Specifically, the effective amount of the pharmaceutical composition of the present invention may depend on the patient's age, sex, condition and body weight, the rate of absorption of the active ingredient in the body, the inactivation rate, the rate of excretion, disease type or drug used in combination and can be administered generally at 0.001 to 150 mg, and preferably 0.01 to 100 mg per kg of body weight daily or every other day, or can be divided into one or three daily administrations. However, the effective amount may vary depending on the route of administration, the severity of obesity, sex, body weight, or age, and therefore the scope of the present invention is not limited by the dose of any way.

Además, la presente invención proporciona un método para tratar una enfermedad inflamatoria, que incluye administrar la composición farmacéutica a un sujeto. El término "sujeto" se refiere a una enfermedad objetivo que ha de tratarse y, más específicamente, un mamífero, tal como un humano, o un primate no humano, un ratón, una rata, un perro, un gato, un caballo y una vaca.Furthermore, the present invention provides a method of treating an inflammatory disease, which includes administering the pharmaceutical composition to a subject. The term "subject" refers to a target disease to be treated and, more specifically, a mammal, such as a human, or a non-human primate, a mouse, a rat, a dog, a cat, a horse, and a cow.

En lo sucesivo en el presente documento, para ayudar a comprender la presente invención, se desvelarán realizaciones de ejemplo. Sin embargo, los siguientes ejemplos se proporcionan meramente para comprender más fácilmente la presente invención y el alcance de la presente invención no se limita a los ejemplos.Hereinafter, to aid in understanding the present invention, exemplary embodiments will be disclosed. However, the following examples are provided merely to more easily understand the present invention, and the scope of the present invention is not limited to the examples.

[Ejemplos][Examples]

Ejemplo 1. Preparación de 4-(4-(3-(A/-fen¡lpentanamido)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de tere-butilo (LMT-693)Example 1. Preparation of 4- (4- (3- (A / -phenylpentanamido) prop-1-¡n¡l) benzo¡l) piperaz¡n-1-carboxylate tere-butyl (LMT-693)

Etapa 1: Preparación de N-fenilpentanoamidaStep 1: Preparation of N-phenylpentanoamide

Se disolvió anilina (0,98 ml, 10,74 mmol) en diclorometano (20 ml) y, después, la mezcla se enfrió en hielo. Se añadió trietilamina (3,00 ml, 21,48 mmol) a la mezcla y, después, la mezcla se agitó durante 5 minutos. Se añadió cloruro de valeroílo (2,60 ml, 21,48 mmol) a la misma temperatura, el hielo se retiró y la mezcla se agitó a temperatura ambiente durante 2 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido de este modo se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=10:1), obteniendo de este modo N-fenilpentanoamida (1,88 g, rendimiento del 99 %).Aniline (0.98 ml, 10.74 mmol) was dissolved in dichloromethane (20 ml), and then the mixture was cooled on ice. Triethylamine (3.00 ml, 21.48 mmol) was added to the mixture, and then the mixture was stirred for 5 minutes. Valeroyl chloride (2.60 ml, 21.48 mmol) was added at the same temperature, the ice was removed and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue thus obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 10: 1), thereby obtaining N-phenylpentanoamide (1.88 g, 99% yield).

Etapa 2: Preparación de 4-(4-bromobenzo¡l)p¡peraz¡na-1-carbox¡lato de tere-butiloStep 2: Preparation of tere-butyl 4- (4-bromobenzol) piperazine-1-carboxylate

Se diluyeron ácido 4-bromobenzoico (901 mg, 4,48 mmol) y piperazin-1-carboxilato de fere-butilo (1,00 g, 5,37 mmol) en NW-dimetilformamida (DMF; 15 ml) y la mezcla se agitó durante 5 minutos. Se añadieron hexafluorofosfato de 3-óxido de 1-[b¡s(d¡met¡lam¡no)met¡leno]-1H-1,2,3-tr¡azolo[4,5-b]p¡r¡d¡n¡o (HATU; 2,04 g, 5,37 mmol) y N,N-diisopropiletilamina (DIPEA; 2,34 ml, 13,44 mmol) a la mezcla y la mezcla se agitó a temperatura ambiente durante 15 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido de este modo se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=2:1), obteniendo de este modo 4-(4-bromobenzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (1,56 g, rendimiento del 94 %).4-Bromobenzoic acid (901 mg, 4.48 mmol) and fere-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol) were diluted in NW-dimethylformamide (DMF; 15 ml) and the mixture was stirred for 5 minutes. 1- [b¡s (dimethylamine) methyl] -1H-1,2,3-tr¡azolo [4,5-b] p¡r¡ 3-oxide hexafluorophosphate were added. d¡no (HATU; 2.04 g, 5.37 mmol) and N, N- diisopropylethylamine (DIPEA; 2.34 ml, 13.44 mmol) to the mixture and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue thus obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (Hex: EA = 2: 1), thereby obtaining fer-butyl 4- (4-bromobenzo¡l) p¡peraz¡n-1-carboxylate (1.56 g, 94% yield).

Etapa 3: Preparación de 4-(4-(3-h¡drox¡prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butiloStep 3: Preparation of 4- (4- (3-hydrox¡prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxyphere-butyllate

El 4-(4-bromobenzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (1,00 g, 2,71 mmol) obtenido en la Etapa 2 y alcohol propargílico (0,32 ml, 5,42 mmol) se disolvieron en trietilamina (12 ml), y la mezcla se agitó durante 5 minutos. Se añadieron dicloruro de bis^rifenilfosfina^aladio (II) (190 mg, 0,271 mmol) y yoduro de cobre (I) (52 mg, 0,271 mmol) a la mezcla, la mezcla se calentó a 60 °C y se sometió a reflujo para su agitación durante 17 horas. La mezcla de reacción se enfrió a temperatura ambiente, se concentró a presión reducida, y el residuo obtenido de este modo se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=2:1), obteniendo de este modo 4-(4-(3-h¡drox¡prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (850 mg, rendimiento del 91 %).Fere-butyl 4- (4-bromobenzol) pi-perazin-1-carboxylate (1.00 g, 2.71 mmol) obtained in Step 2 and propargyl alcohol (0.32 ml, 5.42 mmol) were dissolved in triethylamine (12 ml), and the mixture was stirred for 5 minutes. Bis-rifenylphosphine-aladium (II) dichloride (190 mg, 0.271 mmol) and copper (I) iodide (52 mg, 0.271 mmol) were added to the mixture, the mixture was heated to 60 ° C and refluxed. for stirring for 17 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue thus obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 2: 1), thereby obtaining 4- (4- (3-hydrox¡prop-1-¡n¡l) benzo¡l ) Fere-butyl pi-perazin-1-carboxylate (850 mg, 91% yield).

Etapa 4: Preparación de 4-(4-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butiloStep 4: Preparation of 4- (4- (3- (methylsulfon¡lox¡) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxyphere-butyllate

El 4-(4-(3-h¡drox¡prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (600 mg, 1,74 mmol) obtenido en la Etapa 3 se disolvió en diclorometano (8 ml) y la mezcla se enfrió en hielo. Se añadió trietilamina (0,36 ml, 2,61 mmol) a la mezcla y la mezcla se agitó durante 5 minutos. Se añadió cloruro de metanosulfonilo (0,15 ml, 1,92 mmol) a la misma temperatura, el hielo se retiró y la mezcla se agitó a temperatura ambiente durante 30 minutos. La solución de reacción se concentró a presión reducida y el residuo obtenido de este modo se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=2:1), obteniendo de este modo 4-(4-(3-(metilsulfoniloxi)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (662 mg, rendimiento del 90 %).Fere-butyl 4- (4- (3-hydrox¡prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate (600 mg, 1.74 mmol) obtained in Step 3 was dissolved in dichloromethane (8 ml) and the mixture was cooled in ice. Triethylamine (0.36 ml, 2.61 mmol) was added to the mixture and the mixture was stirred for 5 minutes. Methanesulfonyl chloride (0.15 ml, 1.92 mmol) was added at the same temperature, the ice was removed and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue thus obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (Hex: EA = 2: 1), thereby obtaining 4- (4- (3- (methylsulfonyloxy) prop-1-¡n¡l) benzo¡l) Fere-butyl piperazin-1-carboxylate (662 mg, 90% yield).

Etapa 5: Preparación de 4-(4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo La N-fenilpentanoamida (185 mg, 1,04 mmol) obtenida en la Etapa 1 e hidruro de sodio (NaH; 75 mg, 3,12 mmol) se enfriaron en hielo y, después, se añadió tetrahidrofurano (THF; 8 ml), seguido de agitación durante 30 minutos. El 4-(4-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (662 mg, 1,57 mmol) obtenido en la Etapa 4 se añadió a la mezcla, el hielo se retiró y la mezcla se agitó a temperatura ambiente durante 17 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido de este modo se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=4:1), obteniendo de este modo un producto final, 4-(4-(3-(W-fen¡lpentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (382 mg, rendimiento del 73 %). RMN de 1H (CDCla, 500 MHz) 87,40-7,20 (9H, m), 4,65 (2H, s), 3,62-3,32 (8H, a), 2,02-1,97 (2H, t), 1,52-1,48 (2H, m), 1,40 (9H, s), 1,19-1,12 (2H, m), 0,76-0,72 (3H, t).Step 5: Preparation of Fere-butyl 4- (4- (3- (N-phenylpentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate The N-phenylpentaneamide (185 mg, 1.04 mmol) obtained in Step 1 and sodium hydride (NaH; 75 mg, 3.12 mmol) were cooled on ice, and then tetrahydrofuran (THF; 8 ml) was added , followed by stirring for 30 minutes. Fere-butyl 4- (4- (3- (methylsulfon¡lox¡) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate (662 mg, 1 57 mmol) obtained in Step 4 was added to the mixture, the ice was removed and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue thus obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (Hex: EA = 4: 1), thereby obtaining a final product, 4- (4- (3- (W-phenylpentane) prop-1 -¡N¡l) benzo¡l) p¡peraz¡n-1-carboxylic acid ferr-butyllate (382 mg, 73% yield). 1H NMR (CDCla, 500 MHz) 87.40-7.20 (9H, m), 4.65 (2H, s), 3.62-3.32 (8H, a), 2.02-1, 97 (2H, t), 1.52-1.48 (2H, m), 1.40 (9H, s), 1.19-1.12 (2H, m), 0.76-0.72 ( 3H, t).

Ejemplo 2. Preparación de N-fenil-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanamida (LMT-694)Example 2. Preparation of N- phenyl -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanamide (LMT-694)

El 4-(4-(3-(W-fen¡lpentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de fere-butilo (754 mg, 1,50 mmol) obtenido en el Ejemplo 1 se disolvió en acetonitrilo (15 ml) y la mezcla se agitó a temperatura ambiente durante 5 minutos. Se añadió clorhidrato mixto de dioxano (4 N; 3,73 ml) a la mezcla, y la mezcla se agitó a la misma temperatura durante 1,5 horas. La solución de reacción se concentró a presión reducida, y un residuo obtenido de este modo se purificó mediante cromatografía en columna sobre gel de sílice (CH2Ch:MeOH=50:1), obteniendo de este modo un producto final, W-fenil-W-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida (363 mg, rendimiento del 60 %).Fere-butyl 4- (4- (3- (W-phenylpentaneamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate (754 mg, 1.50 mmol) obtained in Example 1 was dissolved in acetonitrile (15 ml) and the mixture was stirred at room temperature for 5 minutes. Mixed dioxane hydrochloride (4N; 3.73 ml) was added to the mixture, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and a thus obtained residue was purified by silica gel column chromatography (CH2Ch: MeOH = 50: 1), thereby obtaining a final product, W-phenyl-W - (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide (363 mg, 60% yield).

RMN de 1H (CDCla, 500 MHz) 87,48-7,30 (9H, m), 4,73 (2H, s), 3,73-3,39 (4H, a), 2,97-2,86 (4H, a), 2,09-2,06 (2H, t), 1,60-1,54 (2H, m), 1,25-1,19 (2H, m), 0,83-0,80 (3H, t).1H NMR (CDCla, 500 MHz) 87.48-7.30 (9H, m), 4.73 (2H, s), 3.73-3.39 (4H, a), 2.97-2, 86 (4H, a), 2.09-2.06 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83- 0.80 (3H, t).

Ejemplo 3. Preparación de W-(3-(4-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-W-fenilpentanamida (LMT-692) La W-fenil-A/-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida (33,3 mg, 0,072 mmol) obtenida en el Ejemplo 2 e hidróxido de potasio (KOH; 9,09 mg, 0,108 mmol) se disolvieron en A/,W-dimetilformamida (DMF; 1 ml) y la mezcla se agitó a temperatura ambiente durante 5 minutos. Se añadió yodometano (9 pl, 0,144 mmol) a la mezcla y la mezcla se agitó a la misma temperatura durante 17 horas. La solución de reacción se concentró a presión reducida y un residuo obtenido de este modo se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (CH2Ch:MeOH=20:1), obteniendo de este modo un producto final, W-(3-(4-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida (6 mg, rendimiento del 20 %). RMN de 1H (CDCla, 400 MHz) 87,40-7,21 (9H, m), 4,65 (2H, s), 3,71-3,34 (4H, a), 2,41-2,25 (4H, a), 2,25 (3H, s), 2,02-1,99 (2H, t), 1,54-1,46 (2H, m), 1,18-1,12 (2H, m), 0,76­ 0,71 (3H, t).Example 3. Preparation of W- (3- (4- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -W-phenylpentanamide (LMT-692) W-phenyl-A / - (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide (33.3 mg, 0.072 mmol) obtained in Example 2 and potassium hydroxide (KOH; 9.09 mg, 0.108 mmol) were dissolved in A /, W-dimethylformamide (DMF; 1 ml) and the mixture was stirred at room temperature for 5 minutes. Iodomethane (9 µl, 0.144 mmol) was added to the mixture and the mixture was stirred at the same temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and a residue thus obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (CH2Ch: MeOH = 20: 1), thereby obtaining a final product, W- (3- (4- (4-methylpiperazine-1-carbonyl) phenyl) prop -2-ynyl) -N-phenylpentanoamide (6 mg, 20% yield). 1H NMR (CDCla, 400 MHz) 87.40-7.21 (9H, m), 4.65 (2H, s), 3.71-3.34 (4H, a), 2.41-2, 25 (4H, a), 2.25 (3H, s), 2.02-1.99 (2H, t), 1.54-1.46 (2H, m), 1.18-1.12 ( 2H, m), 0.76 0.71 (3H, t).

Ejemplo 4. Preparación de W-(3-(4-(4-etilpiperazin-1-carbonil)fenil)prop-2-inil)-W-fenilpentanoamida (LMT-695) La W-fenil-A/-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida (24,8 mg, 0,061 mmol) obtenida en el Ejemplo 3 e hidróxido de potasio (8,62 mg, 0,154 mmol) se disolvieron en A/,W-dimetilformamida (DMF; 1 ml) y la mezcla se agitó a temperatura ambiente durante 5 minutos. Se añadió yodoetano (20 pl, 0,246 mmol) a la mezcla y la mezcla se agitó a la misma temperatura durante 17 horas. La solución de reacción se concentró a presión reducida y un residuo obtenido de este modo se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (CH2Ch:MeOH = 20:1), obteniendo de este modo un producto final, A/-(3-(4-(4-etilpiperazin-1-carbonil)fenil)prop-2-inil)-W-fenilpentanoamida (17,9 mg, rendimiento del 68 %). RMN de 1H (CDCh, 400 MHz) 87,40-7,20 (9H, m), 4,65 (2H, s), 3,73-3,35 (4H, a), 2,44-2,31 (6H, m), 2,03-1,99 (2H, t), 1,54-1,46 (2H, m), 1,20-1,13 (2H, m), 1,05-1,01 (3H, t), 0,78­ 0,73 (3H, t).Example 4. Preparation of W- (3- (4- (4-ethylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -W-phenylpentanoamide (LMT-695) W-phenyl-A / - (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide (24.8 mg, 0.061 mmol) obtained in Example 3 and potassium hydroxide (8.62 mg, 0.154 mmol) were dissolved in A /, W-dimethylformamide (DMF; 1 ml) and the mixture was stirred at room temperature for 5 minutes. Iodoethane (20 µl, 0.246 mmol) was added to the mixture and the mixture was stirred at the same temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and a residue thus obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Ch: MeOH = 20: 1), thereby obtaining a final product, A / - (3- (4- (4-ethylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -W-phenylpentanoamide (17.9 mg, 68% yield). 1H NMR (CDCh, 400 MHz) 87.40-7.20 (9H, m), 4.65 (2H, s), 3.73-3.35 (4H, br), 2.44-2, 31 (6H, m), 2.03-1.99 (2H, t), 1.54-1.46 (2H, m), 1.20-1.13 (2H, m), 1.05- 1.01 (3H, t), 0.78 0.73 (3H, t).

Ejemplo 5. Preparación de W-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-A/-fenilpentanoamida (LMT-696) La W-fenil-W-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida (106 mg, 0,263 mmol) obtenida en el Ejemplo 2 y bicarbonato de sodio (27 mg, 0,316 mmol) se enfriaron en hielo y, después, se añadió W,W-dimetilformamida (DMF; 2 ml), seguido de agitación durante 1 hora. Se añadió 2-yodopropano (30 pl, 0,316 mmol) a la mezcla, el hielo se retiró y, después, la mezcla se calentó a 60 °C, se sometió a reflujo y se agitó durante 24 horas. La solución de reacción se enfrió a temperatura ambiente y se concentró a presión reducida y un residuo obtenido de este modo se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA:MeOH:TEA=12:12:1:0,1), obteniendo de este modo un producto final, A/-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-A/-fenilpentanoamida (66,8 mg, rendimiento del 57 %).Example 5. Preparation of W- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -A / -phenylpentanoamide (LMT-696) W-phenyl-W- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide (106 mg, 0.263 mmol) obtained in Example 2 and sodium bicarbonate (27 mg, 0.316 mmol) were cooled on ice, and then W, W-dimethylformamide (DMF; 2 ml) was added, followed by stirring for 1 hour. 2-Iodopropane (30 µl, 0.316 mmol) was added to the mixture, the ice was removed, and then the mixture was heated to 60 ° C, refluxed and stirred for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and a residue thus obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA: MeOH: TEA = 12: 12: 1: 0.1), thereby obtaining a final product, A / - (3- (4- ( 4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -A / -phenylpentanoamide (66.8 mg, 57% yield).

RMN de 1H (CDCh, 500 MHz) 87,47-7,30 (9H, m), 4,73 (2H, s), 3,78-3,40 (4H, a), 2,75-2,72 (1H, m), 2,59-2,44 (4H, a), 2,09-2,06 (2H, t), 1,59-1,56 (2H, m), 1,25-1,20 (2H, m), 1,06-1,04 (6H, d), 0,83-0,80 (3H, t).1H NMR (CDCh, 500 MHz) 87.47-7.30 (9H, m), 4.73 (2H, s), 3.78-3.40 (4H, a), 2.75-2, 72 (1H, m), 2.59-2.44 (4H, a), 2.09-2.06 (2H, t), 1.59-1.56 (2H, m), 1.25- 1.20 (2H, m), 1.06-1.04 (6H, d), 0.83-0.80 (3H, t).

Ejemplo 6. Preparación de A/-(3-(4-(4-(2-hidroxietil)piperazin-1-carbonil)fenil)prop-2-inil)-W-fenilpentanoamida (LMT-827)Example 6. Preparation of A / - (3- (4- (4- (2-hydroxyethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -W-phenylpentanoamide (LMT-827)

La A/-fenil-W-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida (56 mg, 0,139 mmol) obtenida en el Ejemplo 2 y carbonato de potasio (77 mg, 0,556 mmol) se disolvieron en acetonitrilo (3 ml) y la mezcla se agitó a temperatura ambiente durante 5 minutos. Se añadió 2-bromoetanol (99 pl, 1,39 mmol) a la mezcla, el hielo se retiró y, después, la mezcla se calentó a 60 °C, se sometió a reflujo y se agitó durante 17 horas. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (CH2Ch:MeOH=50:1), obteniendo de este modo un producto final, W-(3-(4-(4-(2-hidroxietil)piperazin-1-carbonil)fenil)prop-2-inil)-A/-fenilpentanoamida (52 mg, rendimiento del 84 %).The A / -phenyl-W- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide (56 mg, 0.139 mmol) obtained in Example 2 and potassium carbonate (77 mg, 0.556 mmol) were dissolved in acetonitrile (3 ml) and the mixture was stirred at room temperature for 5 minutes. 2-Bromoethanol (99 µl, 1.39 mmol) was added to the mixture, the ice was removed, and then the mixture was heated to 60 ° C, refluxed and stirred for 17 hours. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Ch: MeOH = 50: 1), thereby obtaining a final product, W- (3- (4- (4- (2-hydroxyethyl) piperazine-1- carbonyl) phenyl) prop-2-ynyl) -A / -phenylpentanoamide (52 mg, 84% yield).

RMN de 1H (CDCh, 500 MHz) 87,48-7,30 (9H, m), 4,73 (2H, s), 3,79 (2H, a), 3,66-3,64 (2H, t), 3,43 (2H, a), 2,60­ 2,46 (7H, a), 2,10-2,07 (2H, t), 1,59-1,56 (2H, m), 1,25-1,22 (2H, m), 0,83-0,80 (3H, t). 1H NMR (CDCh, 500 MHz) 87.48-7.30 (9H, m), 4.73 (2H, s), 3.79 (2H, a), 3.66-3.64 (2H, t), 3.43 (2H, a), 2.60 2.46 (7H, a), 2.10-2.07 (2H, t), 1.59-1.56 (2H, m), 1.25-1.22 (2H, m), 0.83-0.80 (3H, t).

Ejemplo 7. Preparación de N-(3-(4-(4-(c¡cloprop¡lmet¡l)p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (LMT-828)Example 7. Preparation of N- (3- (4- (4- (cyclopropylmethyl) piperazin-1-carbonl) phenyl) prop-2-nil) -N-phenylpentaneamide (LMT-828)

La N-fen¡l-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obtenida en el Ejemplo 2 y carbonato de potas¡o (51 mg, 0,372 mmol) se d¡solv¡eron en N,N-d¡met¡lformam¡da (DMF; 2 ml) y la mezcla se ag¡tó a temperatura amb¡ente durante 5 m¡nutos. Se añad¡ó bromuro de c¡cloprop¡lmet¡lo (15 pl, 0,145 mmol) a la mezcla, la mezcla se calentó a 80 °C, se somet¡ó a reflujo y se ag¡tó durante 4 horas. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (CH2Cl2:MeOH=50:1), obten¡endo de este modo un producto f¡nal, N-(3-(4-(4-(c¡cloprop¡lmet¡l)p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanam¡da (16 mg, rend¡m¡ento del 28 %).The N-phenylN- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (50 mg, 0.124 mmol) obtained in Example 2 and potassium carbonate (51 mg, 0.372 mmol) were dissolved in N, Nd, methylformamide (DMF; 2 ml) and the mixture was stirred at room temperature. ente for 5 minutes. Cyclopropylmethyl bromide (15 µl, 0.145 mmol) was added to the mixture, the mixture was heated to 80 ° C, refluxed and stirred for 4 hours. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Cl2: MeOH = 50: 1), thus obtaining a final product, N- (3- (4- (4- (cyclopropylmethyl) p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-phenylpentanam¡da (16 mg, yield 28%).

RMN de 1H (CDCh,500 MHz) 87,48-7,28 (9H, m), 4,73 (2H, s), 3,82-3,45 (4H, a), 2,63-2,49 (4H, a), 2,32-2,31 (2H, d), 2,09-2,06 (2H, t), 1,60-1,56 (2H, m), 1,25-1,20 (3H, m), 0,83-0,80 (3H, t), 0,55-0,53 (2H, m), 0,12-0,11 (2H, m). Ejemplo 8. Preparac¡ón de N-(3-(4-(4-c¡clohex¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (LMT-830) Un producto f¡nal, N-(3-(4-(4-c¡clohex¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da, se obtuvo (20 mg, rend¡m¡ento del 33 %) med¡ante el m¡smo método descr¡to en el Ejemplo 7 usando la N-fen¡l-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obten¡da en el Ejemplo 2 y yodoc¡clohexano (19 pl, 0,145 mmol).1H NMR (CDCh, 500 MHz) 87.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.45 (4H, a), 2.63-2, 49 (4H, a), 2.32-2.31 (2H, d), 2.09-2.06 (2H, t), 1.60-1.56 (2H, m), 1.25- 1.20 (3H, m), 0.83-0.80 (3H, t), 0.55-0.53 (2H, m), 0.12-0.11 (2H, m). Example 8. Preparation of N- (3- (4- (4-cyclohex¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N- phenylpentaneamide (LMT-830) A final product, N- (3- (4- (4-cyclohex¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2 -¡N¡l) -N-phenylpentaneamide, (20 mg, 33% yield) was obtained by the same method described in Example 7 using the N-fen ¡LN- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (50 mg, 0.124 mmol) obtained in the Example 2 and iodocyclohexane (19 µl, 0.145 mmol).

RMN de 1H (CDCla, 500 MHz) 87,48-7,31 (9H, m), 4,73 (2H, s), 3,77-3,39 (4H, a), 2,63-2,49 (4H, a), 2,31-2,28 (1H, m), 2,09-2,06 (2H, m), 1,91-1,79 (4H, m), 1,65-1,54 (3H, m), 1,28-1,16 (6H, m), 1,13-1,08 (1H, m), 0,83-0,80 (3H, t). Ejemplo 9. Preparac¡ón de A/-(3-(4-(4-(c¡clohex¡lmet¡l)p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-A/-fen¡lpentanam¡da (LMT-831)1H NMR (CDCla, 500 MHz) 87.48-7.31 (9H, m), 4.73 (2H, s), 3.77-3.39 (4H, a), 2.63-2, 49 (4H, a), 2.31-2.28 (1H, m), 2.09-2.06 (2H, m), 1.91-1.79 (4H, m), 1.65- 1.54 (3H, m), 1.28-1.16 (6H, m), 1.13-1.08 (1H, m), 0.83-0.80 (3H, t). Example 9. Preparation of A / - (3- (4- (4- (cyclohexlmetal) p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n ¡L) -A / -phenylpentanam¡da (LMT-831)

Un producto f¡nal, N-(3-(4-(4-(c¡clohex¡lmet¡l)p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da, se obtuvo (35 mg, rend¡m¡ento del 56 %) med¡ante el m¡smo método descr¡to en el Ejemplo 7 usando la N-fen¡l-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obten¡da en el Ejemplo 2 y bromomet¡lc¡clohexano (20 pl, 0,145 mmol).An end product, N- (3- (4- (4- (cyclohexylmetal) p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l ) -N-phenylpentaneamide, (35 mg, yield 56%) was obtained by the same method described in Example 7 using the N-phenylN- (3 - (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (50 mg, 0.124 mmol) obtained in Example 2 and bromomet¡ Cyclohexane (20 µl, 0.145 mmol).

RMN de 1H (CDCla, 500 MHz) 87,48-7,28 (9H, m), 4,73 (2H, s), 3,76-3,38 (4H, a), 2,45-2,31 (4H, a), 2,15-2,13 (2H, m), 2,09-2,06 (2H, m), 1,77-1,66 (5H, m), 1,59-1,56 (2H, m), 1,47-1,45 (1H, m), 1,25-1,17 (5H, m), 0,90-0,80 (5H, t). Ejemplo 10. Preparac¡ón de N-(3-(4-(4-¡sobut¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanam¡da (LMT-832) Un producto f¡nal, N-(3-(4-(4-¡sobut¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da, se obtuvo (34 mg, rend¡m¡ento del 60 %) med¡ante el método descr¡to en el Ejemplo 7 usando la N-fen¡l-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obten¡da en el Ejemplo 2 y 1-yodo-2-met¡lpropano (17 pl, 0,145 mmol).1H NMR (CDCla, 500 MHz) 87.48-7.28 (9H, m), 4.73 (2H, s), 3.76-3.38 (4H, a), 2.45-2, 31 (4H, a), 2.15-2.13 (2H, m), 2.09-2.06 (2H, m), 1.77-1.66 (5H, m), 1.59- 1.56 (2H, m), 1.47-1.45 (1H, m), 1.25-1.17 (5H, m), 0.90-0.80 (5H, t). Example 10. Preparation of N- (3- (4- (4-¡sobut¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-fen ¡Lpentanam¡da (LMT-832) A final product, N- (3- (4- (4-¡sobut¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡ n¡l) -N-phenylpentaneamide, (34 mg, 60% yield) was obtained by the method described in Example 7 using the N-phenylN- (3 - (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (50 mg, 0.124 mmol) obtained in Example 2 and 1- Iodo-2-methylpropane (17 µl, 0.145 mmol).

RMN de 1H (CDCh, 500 MHz)8 7,47-7,28 (9H, m), 4,73 (2H, s), 3,76-3,39 (4H, a), 2,46-2,32 (4H, a), 2,11-2,07 (4H, m), 1,79-1,76 (1H, m), 1,59-1,56 (2H, m), 1,25-1,20 (2H, m), 0,91-0,89 (6H, d), 0,83-0,80 (3H, t).1H NMR (CDCh, 500 MHz) 8 7.47-7.28 (9H, m), 4.73 (2H, s), 3.76-3.39 (4H, a), 2.46-2 , 32 (4H, a), 2.11-2.07 (4H, m), 1.79-1.76 (1H, m), 1.59-1.56 (2H, m), 1.25 -1.20 (2H, m), 0.91-0.89 (6H, d), 0.83-0.80 (3H, t).

Ejemplo 11. Preparac¡ón de N-fen¡l-N-(3-(4-(4-(prop-2-¡n¡l)p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanam¡da (LMT-833)Example 11. Preparation of N-phenylN- (3- (4- (4- (prop-2-innl) piperazin-1-carbonl) phenyl) prop- 2-¡n¡l) pentanam¡da (LMT-833)

La N-fen¡l-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obten¡da en el Ejemplo 2 y carbonato de potas¡o (51 mg, 0,372 mmol) se d¡solv¡eron en N,N-d¡met¡lformam¡da (DMF; 2 ml) y la mezcla se ag¡tó a temperatura amb¡ente durante 5 m¡nutos. Se añad¡ó bromuro de proparg¡lo (12 pl, 0,145 mmol) a la mezcla y la mezcla se ag¡tó a temperatura amb¡ente durante 17 horas. La soluc¡ón de reacc¡ón se f¡ltró para ret¡rar un sól¡do y se concentró a pres¡ón reduc¡da y el concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (CH2Ch:MeOH=100:1), obten¡endo de este modo un producto final, N-fen¡l-N-(3-(4-(4-(prop-2-¡n¡l)p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (28 mg, rend¡m¡ento del 51 %).N-phenylN- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (50 mg, 0.124 mmol) obtained The one given in Example 2 and potassium carbonate (51 mg, 0.372 mmol) were dissolved in N, N, dimethylformamide (DMF; 2 mL) and the mixture was stirred at room temperature. environment for 5 minutes. Propargyl bromide (12 µl, 0.145 mmol) was added to the mixture and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered to remove a solid and concentrated under reduced pressure and the concentrate was purified by column chromatography on silica gel. ce (CH2Ch: MeOH = 100: 1), thus obtaining a final product, N-phen¡lN- (3- (4- (4- (prop-2-¡n¡l) p¡peraz¡ n-1-carbonl) phenl) prop-2-nl) pentanoamide (28 mg, 51% yield).

RMN de 1H (CDCls, 500 MHz) 87,48-7,28 (9H, m), 4,73 (2H, s), 3,82-3,44 (4H, a), 3,36 (2H, s), 2,65-2,51 (4H, a), 2,30 (1H, s), 2,10-2,07 (2H, m), 1,60-1,54 (2H, m), 1,26-1,19 (2H, m), 0,83-0,80 (3H, t).1H NMR (CDCls, 500 MHz) 87.48-7.28 (9H, m), 4.73 (2H, s), 3.82-3.44 (4H, br), 3.36 (2H, s), 2.65-2.51 (4H, a), 2.30 (1H, s), 2.10-2.07 (2H, m), 1.60-1.54 (2H, m) , 1.26-1.19 (2H, m), 0.83-0.80 (3H, t).

Ejemplo 12. Preparac¡ón de N-(3-(4-(4-c¡anop¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanam¡da (LMT-829) La N-fen¡l-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obten¡da en el Ejemplo 2 y c¡anuro de tr¡met¡ls¡l¡lo (49 pl, 0,372 mmol) se d¡solv¡eron en aceton¡tr¡lo (2 ml) y la mezcla se ag¡tó a temperatura amb¡ente durante 5 m¡nutos. Se añad¡ó h¡pocloruro de sod¡o (43 pl, 0,620 mmol) a la mezcla, la mezcla se calentó a 80 °C, se somet¡ó a reflujo y se ag¡tó durante 12 horas. La soluc¡ón de reacc¡ón se enfr¡ó a temperatura amb¡ente, se f¡ltró para ret¡rar un sól¡do y se concentró a pres¡ón reduc¡da. El res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (CH2Ch:MeOH=200:1), obten¡endo de este modo un producto f¡nal, N-(3-(4-(4-c¡anop¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanam¡da (11 mg, rend¡m¡ento del 21 %). Example 12. Preparation of N- (3- (4- (4-c¡anop¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-phen¡ lpentanamida (LMT-829) N-phenylN- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoam¡da (50 mg, 0.124 mmol) obtained in Example 2 and trimetyl cyanide (49 µl, 0.372 mmol) were dissolved in acetonitrile (2 ml) and the mixture was stirred at room temperature for 5 minutes. Sodium hydrochloride (43 µl, 0.620 mmol) was added to the mixture, the mixture was heated to 80 ° C, refluxed and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered to remove a solid, and concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Ch: MeOH = 200: 1), thus obtaining a final product, N- (3- (4- (4-c¡anop¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-phenylpentanam¡da (11 mg, yield 21% ).

RMN de 1H (CDCh,500 MHz) 57,48-7,30 (9H, m), 4,73 (2H, s), 3,81-3,26 (8H, a), 2,09-2,06 (2H, t), 1,60-1,54 (2H, m), 1,25-1,19 (2H, m), 0,83-0,80 (3H, t).1H NMR (CDCh, 500 MHz) 57.48-7.30 (9H, m), 4.73 (2H, s), 3.81-3.26 (8H, a), 2.09-2, 06 (2H, t), 1.60-1.54 (2H, m), 1.25-1.19 (2H, m), 0.83-0.80 (3H, t).

Ejemplo 13. Preparación de 4-(4-(3-(N-(3-fluorofen¡l)pentanam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-butilo (LMT-884)Example 13. Preparation of 4- (4- (3- (N- (3-fluorophenyl) pentanamido) prop-1-¡n¡l) benzo¡l) piperaz¡n-1-carbox¡ tert- butyllate (LMT-884)

Etapa 1: Preparac¡ón de A/-(3-fluorofen¡l)pentanam¡daStage 1: Preparation of A / - (3-fluorophenil) pentanamide

Se obtuvo N-(3-fluorofen¡l)pentanoam¡da (1,74 g, rend¡m¡ento del 99 %) usando 3-fluoroan¡l¡na (0,87 ml, 9,00 mmol) y cloruro de valeroílo (2,18 ml, 18,00 mmol).N- (3-fluorophenyl) pentanoamide (1.74 g, 99% yield) was obtained using 3-fluoroaniline (0.87 ml, 9.00 mmol) and chloride of valeroyl (2.18 ml, 18.00 mmol).

Etapa 2: Preparac¡ón de 4-(4-(3-(A/-(3-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-butíloStep 2: Preparation of 4- (4- (3- (A / - (3-fluorophenyl) pentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1 -carbox¡lato tert - butyl

Un producto f¡nal, 4-(4-(3-(N-(3-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo, se obtuvo (197 mg, rend¡m¡ento del 73 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la N-(3-fluorofen¡l)pentanoam¡da (101 mg, 0,519 mmol) obten¡da en la Etapa 1 y el 4-(4-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (329 mg, 0,779 mmol) obten¡do en la Etapa 4 del Ejemplo 1.An end product, 4- (4- (3- (N- (3-fluorophenyl) pentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carbox Tert-butyllate, (197 mg, 73% yield) was obtained by the same method described in Step 5 of Example 1 using the N- (3-fluorophen ¡L) pentanoamide (101 mg, 0.519 mmol) obtained in Step 1 and the 4- (4- (3- (methylsulfon¡lox¡) prop-1-¡n¡l) benzo¡l ) tert-butyl pi-perazin-1-carboxylate (329 mg, 0.779 mmol) obtained in Step 4 of Example 1.

RMN de 1H (CDCla, 400 MHz) 57,44-7,32 (5H, m), 7,12-7,06 (3H, m), 4,72 (2H, s), 3,73-3,38 (8H, a), 2,10-2,07 (2H, t), 1,59-1,57 (2H, m), 1,47 (9H, s), 1,23-1,20 (2H, m), 0,83-0,80 (3H, t).1H NMR (CDCla, 400 MHz) 57.44-7.32 (5H, m), 7.12-7.06 (3H, m), 4.72 (2H, s), 3.73-3, 38 (8H, a), 2.10-2.07 (2H, t), 1.59-1.57 (2H, m), 1.47 (9H, s), 1.23-1.20 ( 2H, m), 0.83-0.80 (3H, t).

Ejemplo 14. Preparac¡ón de N-(3-fluorofen¡l)-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-885) Un producto f¡nal, N-(3-fluorofen¡l)-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (94 mg, rend¡m¡ento del 58 %) med¡ante el m¡smo método descr¡to en el Ejemplo 12 usando el 4-(4-(3-(N-(3-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (200 mg, 0,383 mmol) obten¡do en el Ejemplo 13.Example 14. Preparation of N- (3-fluorophenyl) -N- (3- (4- (p¡peraz¡n-1-carbon¡l) phenl) prop-2-¡n¡l ) Pentanoamide (LMT-885) A final product, N- (3-fluorophenyl) -N- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide, (94 mg, 58% yield) was obtained by the same method described in Example 12 using the 4- (4- Tert-Butyl (3- (N- (3-fluorophenyl) pentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate (200 mg , 0.383 mmol) obtained in Example 13.

RMN de 1H (CDCla, 400 MHz) 57,45-7,32 (5H, m), 7,15-7,07 (3H, m), 4,72 (2H, s), 3,75-3,37 (4H, a), 2,94-2,80 (4H, a), 2,10-2,07 (2H, t), 1,89 (1H, a), 1,60-1,57 (2H, m), 1,25-1,24 (2H, m), 0,84-0,82 (3H, t).1H NMR (CDCla, 400 MHz) 57.45-7.32 (5H, m), 7.15-7.07 (3H, m), 4.72 (2H, s), 3.75-3, 37 (4H, a), 2.94-2.80 (4H, a), 2.10-2.07 (2H, t), 1.89 (1H, a), 1.60-1.57 ( 2H, m), 1.25-1.24 (2H, m), 0.84-0.82 (3H, t).

Ejemplo 15. Preparac¡ón de N-(3-fluorofen¡l)-N-(3-(4-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-886)Example 15. Preparation of N- (3-fluorophenyl) -N- (3- (4- (4-isopropylp¡peraz¡n-1-carbon¡l) phen¡l) prop-2 -¡N¡l) pentanoam¡da (LMT-886)

Un producto f¡nal, N-(3-fluorofen¡l)-N-(3-(4-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (20 mg, rend¡m¡ento del 40 %) usando la N-(3-fluorofen¡l)-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (46 mg, 0,109 mmol) obten¡da en el Ejemplo 14 y 2-yodopropano (0,375 ml, 3,77 mmol).A final product, N- (3-fluorophenyl) -N- (3- (4- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2- N¡l) pentanoamide, was obtained (20 mg, yield 40%) using the N- (3-fluorophenyl) -N- (3- (4- (p¡peraz¡n -1-carbon (l) phen (l) prop-2-n (l) pentanoamide (46 mg, 0.109 mmol) obtained in Example 14 and 2-iodopropane (0.375 ml, 3.77 mmol) .

RMN de 1H (CDCh, 400 MHz) 57,44-7,32 (5H, m), 7,15-7,06 (3H, m), 4,72 (2H, s), 3,78-3,41 (4H, a), 2,75-2,72 (1H, m), 2,59-2,45 (4H, a), 2,11-2,09 (2H, t), 1,60-1,57 (2H, m), 1,25-1,22 (2H, m), 1,06-1,05 (6H, d), 0,85-0,82 (3H, t). Ejemplo 16. Preparac¡ón de 4-(4-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (LMT-839)1H NMR (CDCh, 400 MHz) 57.44-7.32 (5H, m), 7.15-7.06 (3H, m), 4.72 (2H, s), 3.78-3, 41 (4H, a), 2.75-2.72 (1H, m), 2.59-2.45 (4H, a), 2.11-2.09 (2H, t), 1.60- 1.57 (2H, m), 1.25-1.22 (2H, m), 1.06-1.05 (6H, d), 0.85-0.82 (3H, t). Example 16. Preparation of 4- (4- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-innl) benzol) piperazin-1- tert- butyl carboxylate (LMT-839)

Etapa 1: Preparac¡ón de N-(4-fluorofen¡l)pentanoam¡daStep 1: Preparation of N- (4-fluorophenyl) pentanoamide

Se obtuvo N-(4-fluorofen¡l)pentanoam¡da (174 mg, rend¡m¡ento del 99 %) med¡ante el m¡smo método descr¡to en la Etapa 1 del Ejemplo 1 usando 4-fluoroan¡l¡na (85 pl, 0,90 mmol) y cloruro de valeroílo (0,22 ml, 1,80 mmol).N- (4-fluorophenyl) pentanoamide (174 mg, 99% yield) was obtained by the same method described in Step 1 of Example 1 using 4-fluoroan¡ lina (85 µl, 0.90 mmol) and valeroyl chloride (0.22 ml, 1.80 mmol).

Etapa 2: Preparac¡ón de 4-(4-(3-(N-(4-fluorofen¡l)pentanam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡loStep 2: Preparation of 4- (4- (3- (N- (4-fluorophenyl) pentanamido) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1- tert- butyl carboxylate

Un producto f¡nal, 4-(4-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo, se obtuvo (2,28 g, rend¡m¡ento del 73 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la N-(4-fluorofen¡l)pentanoam¡da (1,17 g, 6,00 mmol) obten¡da en la Etapa 1 y el 4-(4-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (3,80 g, 8,99 mmol) obten¡do en la Etapa 4 del Ejemplo 1.An end product, 4- (4- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-innl) benzoil) piperazin-1-carbox In tert-butyl, (2.28 g, 73% yield) was obtained by the same method described in Step 5 of Example 1 using the N- (4 -fluorophenyl) pentanoamide (1.17 g, 6.00 mmol) obtained in Step 1 and the 4- (4- (3- (meth-lsulfon-lox)) prop-1-n L) benzol) piperazin-1-carboxylate tert-butyl (3.80 g, 8.99 mmol) obtained in Step 4 of Example 1.

RMN de 1H (CDCh, 400 MHz) 57,39-7,29 (6H, m), 7,17-7,14 (2H, m), 4,71 (2H, s), 3,73-3,38 (8H, a), 2,07-2,04 (2H, t), 1,60-1,54 (2H, m), 1,47 (9H, s), 1,25-1,19 (2H, m), 0,84-0,81 (3H, t).1H NMR (CDCh, 400 MHz) 57.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.71 (2H, s), 3.73-3, 38 (8H, a), 2.07-2.04 (2H, t), 1.60-1.54 (2H, m), 1.47 (9H, s), 1.25-1.19 ( 2H, m), 0.84-0.81 (3H, t).

Ejemplo 17. Preparac¡ón de N-(4-fluorofen¡l)-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-840) Un producto f¡nal, N-(4-fluorofen¡l)-N-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (1,06 g, rend¡m¡ento del 58 %) med¡ante el m¡smo método descr¡to en el Ejemplo 12 usando el 4-(4-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (2,28 g, 4,37 mmol) obten¡do en el Ejemplo 16.Example 17. Preparation of N- (4-fluorophenyl) -N- (3- (4- (piperazin-1-carbonl) phenl) prop-2-innl ) pentanoamide (LMT-840) A final product, N- (4-fluorophenyl) -N- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide, (1.06 g, 58% yield) was obtained by the same method described in Example 12 using the 4- ( Tert-butyl (4- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-innl) benzol) piperazin-1-carboxylate 2.28 g, 4.37 mmol) obtained in Example 16.

RMN de 1H (CDCh, 400 MHz) 57,38-7,30 (6H, m), 7,17-7,15 (2H, m), 4,71 (2H, s), 3,77-3,40 (4H, a), 2,96-2,79 (5H, a), 2,06-2,03 (2H, t), 1,57-1,54 (2H, m), 1,25-1,22 (2H, m), 0,84-0,82 (3H, t). 1H NMR (CDCh, 400 MHz) 57.38-7.30 (6H, m), 7.17-7.15 (2H, m), 4.71 (2H, s), 3.77-3, 40 (4H, a), 2.96-2.79 (5H, a), 2.06-2.03 (2H, t), 1.57-1.54 (2H, m), 1.25- 1.22 (2H, m), 0.84-0.82 (3H, t).

Ejemplo 18. Preparación de A/-(4-fluorofen¡l)-A/-(3-(4-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-841)Example 18. Preparation of A / - (4-fluorophenyl) -A / - (3- (4- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2 -¡N¡l) pentanoam¡da (LMT-841)

Un producto f¡nal, W-(4-fluorofen¡l)-W-(3-(4-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (465 mg, rend¡m¡ento del 40 %) med¡ante el m¡smo método descr¡to en el Ejemplo 15 usando la W-(4-fluorofen¡l)-W-(3-(4-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (1,06 g, 2,51 mmol) obten¡da en el Ejemplo 17 y 2-yodopropano (0,375 ml, 3,77 mmol).A final product, W- (4-fluorophenyl) -W- (3- (4- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2- N¡l) pentanoamide, (465 mg, yield 40%) was obtained by the same method described in Example 15 using the W- (4-fluorophenil) -W- (3- (4- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (1.06 g, 2.51 mmol) obtained Given in Example 17 and 2-iodopropane (0.375 ml, 3.77 mmol).

RMN de 1H (CDCla, 400 MHz) 87,37-7,28 (6H, m), 7,17-7,13 (2H, m), 4,71 (2H, s), 3,78-3,40 (4H, a), 2,75-2,72 (1H, m), 2,59-2,45 (4H, a), 2,07-2,04 (2H, t), 1,58-1,55 (2H, m), 1,25-1,21 (2H, m), 1,06-1,04 (6H, d), 0,84-0,81 (3H, t). Ejemplo 19. Preparac¡ón de W-(3-(4-(morfol¡n-4-carbon¡l)fen¡l)prop-2-¡n¡l)-A/-fen¡lpentanoam¡da (LMT-682) Etapa 1: (4-bromofen¡l)(morfol¡no)metanona1H NMR (CDCla, 400 MHz) 87.37-7.28 (6H, m), 7.17-7.13 (2H, m), 4.71 (2H, s), 3.78-3, 40 (4H, a), 2.75-2.72 (1H, m), 2.59-2.45 (4H, a), 2.07-2.04 (2H, t), 1.58- 1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.04 (6H, d), 0.84-0.81 (3H, t). Example 19. Preparation of W- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-inl) -A / -phenylpentaneamide (LMT -682) Stage 1: (4-bromophenyl) (morpholino) methanone

Se obtuvo (4-bromofen¡l)(morfol¡no)metanona (455 mg, rend¡m¡ento del 99 %) med¡ante el mismo método descr¡to en la Etapa 2 del Ejemplo 1 usando ác¡do 4-bromobenzo¡co (340 mg, 1,70 mmol) y morfol¡na (0,18 ml, 2,04 mmol). Etapa 2: Preparac¡ón de (4-(3-h¡drox¡prop-1-¡n¡l)fen¡l)(morfol¡no)metanona(4-Bromophenyl) (morpholin) methanone (455 mg, 99% yield) was obtained by the same method described in Step 2 of Example 1 using acid 4- bromobenzole (340 mg, 1.70 mmol) and morpholin (0.18 ml, 2.04 mmol). Stage 2: Preparation of (4- (3-hydrox¡prop-1-¡n¡l) phen¡l) (morphol) methanone

Se obtuvo (4-(3-h¡drox¡prop-1-¡n¡l)fen¡l)(morfol¡no)metanona (371 mg, rend¡m¡ento del 90 %) med¡ante el m¡smo método descr¡to en la Etapa 3 del Ejemplo 1 usando la (4-bromofen¡l)(morfol¡no)metanona (455 mg, 1,68 mmol) obten¡da en la Etapa 1 y alcohol propargíl¡co (0,196 ml, 3,36 mmol).(4- (3-hydrox¡prop-1-¡n¡l) phen¡l) (morpholin) methanone (371 mg, 90% yield) was obtained by means of the minimum This method described in Step 3 of Example 1 using the (4-bromophenyl) (morpholine) methanone (455 mg, 1.68 mmol) obtained in Step 1 and propargyl alcohol (0.196 ml, 3.36 mmol).

Etapa 3: Preparac¡ón de metanosulfonato de 3-(4-(morfol¡n-4-carbon¡l)fen¡l)prop-2-¡n¡loStep 3: Preparation of 3- (4- (morpholin-4-carbonyl) phenyl) prop-2-nyl methanesulfonate

Se obtuvo metanosulfonato de 3-(4-(morfol¡n-4-carbon¡l)fen¡l)prop-2-¡n¡lo (391 mg, rend¡m¡ento del 80 %) med¡ante el m¡smo método descr¡to en la Etapa 4 del Ejemplo 1 usando la (4-(3-h¡drox¡prop-1-¡n¡l)fen¡l)(morfol¡no)metanona (371 mg, 1,51 mmol) obten¡da en la Etapa 2 y cloruro de metanosulfon¡lo (0,128 ml, 1,66 mmol).3- (4- (morpholin-4-carbonyl) phenyl) prop-2-inyl methanesulfonate (391 mg, 80% yield) was obtained by means of the m The same method as described in Step 4 of Example 1 using (4- (3-hydrox¡prop-1-¡n¡l) phen¡l) (morpholin) methanone (371 mg, 1, 51 mmol) obtained in Step 2 and methanesulfonychloride (0.128 ml, 1.66 mmol).

Etapa 4: Preparac¡ón de A/-(3-(4-(morfol¡n-4-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡daStep 4: Preparation of A / - (3- (4- (morpholin-4-carbon¡l) phen¡l) prop-2-¡n¡l) -N-phenylpentaneamide

Un producto final, W-(3-(4-(morfol¡n-4-carbon¡l)fen¡l)prop-2-¡n¡l)-W-fen¡lpentanoam¡da, se obtuvo (371 mg, rend¡m¡ento del 90 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la A/-fen¡lpentanoam¡da (143 mg, 0,81 mmol) obten¡da en la Etapa 1 del Ejemplo 1 y el metanosulfonato de 3-(4-(morfol¡n-4-carbon¡l)fen¡l)prop-2-¡n¡lo (391 mg, 1,21 mmol) obten¡do en la Etapa 3.A final product, W- (3- (4- (morpholin-4-carbonl) phenyl) prop-2-nil) -W-phenylpentaneamide, was obtained (371 mg , 90% yield) by the same method described in Step 5 of Example 1 using the A / -phentaneamide (143 mg, 0.81 mmol) obtained in Step 1 of Example 1 and the methanesulfonate of 3- (4- (morpholin-4-carbonyl) phenyl) prop-2-inylo (391 mg, 1.21 mmol) obtained do in Stage 3.

RMN de 1H (400 MHz, CDCla) 87,48-7,28 (m, 9H), 4,73 (s, 2H), 3,74-3,66 (a, 6 H), 3,43 (a, 2H), 2,08 (m, 2H), 1,57 (m, 2H), 1,22 (m, 2H), 0,81 (t, 3H).1H NMR (400MHz, CDCla) 87.48-7.28 (m, 9H), 4.73 (s, 2H), 3.74-3.66 (a, 6H), 3.43 (a , 2H), 2.08 (m, 2H), 1.57 (m, 2H), 1.22 (m, 2H), 0.81 (t, 3H).

Ejemplo 20. Preparac¡ón de W-fen¡l-W-(3-(4-(p¡per¡d¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-683) Etapa 1: Preparac¡ón de (4-bromofen¡l)(p¡per¡d¡n-1-¡l)metanonaExample 20. Preparation of W-phen¡lW- (3- (4- (p¡per¡d¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoam¡da (LMT-683) Stage 1: Preparation of (4-bromophenyl) (p¡per¡d¡n-1-¡l) methanone

Se obtuvo (4-bromofen¡l)(p¡per¡d¡n-1-¡l)metanona (458,2 mg, rend¡m¡ento del 100 %) med¡ante el m¡smo método descr¡to en la Etapa 2 del Ejemplo 1 usando ác¡do 4-bromobenzo¡co (318 mg, 1,58 mmol) y p¡per¡d¡na (0,21 ml, 1,90 mmol).(4-bromophenil) (p¡per¡d¡n-1-¡l) methanone (458.2 mg, 100% yield) was obtained by the same method described in Step 2 of Example 1 using 4-bromobenzoic acid (318 mg, 1.58 mmol) and piperidine (0.21 ml, 1.90 mmol).

Etapa 2: Preparac¡ón de (4-(3-h¡drox¡prop-1-¡n¡l)fen¡l)(p¡per¡d¡n-1-¡l)metanonaStage 2: Preparation of (4- (3-hydrox¡prop-1-¡n¡l) phen¡l) (p¡per¡d¡n-1-¡l) methanone

Se obtuvo (4-(3-h¡drox¡prop-1-¡n¡l)fen¡l)(p¡per¡d¡n-1-¡l)metanona (374 mg, rend¡m¡ento del 90 %) med¡ante el m¡smo método descr¡to en la Etapa 3 del Ejemplo 1 usando la (4-bromofen¡l)(p¡per¡d¡na-1-¡l)metanona (458,2 mg, 1,71 mmol) obten¡da en la Etapa 1 y alcohol propargíl¡co (0,199 ml, 3,42 mmol).(4- (3-hydrox¡prop-1-¡n¡l) phen¡l) (p¡per¡d¡n-1-¡l) methanone (374 mg, yield of 90%) by the same method described in Step 3 of Example 1 using (4-bromophenyl) (p¡per¡d¡na-1-¡l) methanone (458.2 mg , 1.71 mmol) obtained in Step 1 and propargyl alcohol (0.199 ml, 3.42 mmol).

Etapa 3: Preparac¡ón de metanosulfonato de 3-(4-(p¡per¡d¡n-1-carbon¡l)fen¡l)prop-2-¡n¡loStep 3: Preparation of 3- (4- (p¡per¡d¡n-1-carbon¡l) phen¡l) prop-2-¡n¡lo methanesulfonate

Se obtuvo metanosulfonato de 3-(4-(p¡per¡d¡n-1-carbon¡l)fen¡l)prop-2-¡n¡lo (396 mg, rend¡m¡ento del 80 %) med¡ante el m¡smo método descr¡to en la Etapa 4 del Ejemplo 1 usando la (4-(3-h¡drox¡prop-1-¡n¡l)fen¡l)p¡r¡d¡n-1-¡l)metanona (374 mg, 1,54 mmol) obten¡da en la Etapa 2 y cloruro de metanosulfon¡lo (0,131 ml, 1,69 mmol).3- (4- (p¡per¡d¡n-1-carbon¡l) phen¡l) prop-2-¡n¡lo methanesulfonate (396 mg, 80% yield) was obtained with Before the same method described in Step 4 of Example 1 using the (4- (3-hydrox¡prop-1-¡n¡l) phen¡l) p¡r¡d¡n- 1-l) methanone (374 mg, 1.54 mmol) obtained in Step 2 and methanesulfony chloride (0.131 ml, 1.69 mmol).

Etapa 4: Preparac¡ón de A/-fen¡l-N-(3-(4-(p¡per¡d¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡daStep 4: Preparation of A / -phenylN- (3- (4- (p¡per¡d¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoam¡ gives

Un producto final, W-fen¡l-W-(3-(4-(p¡per¡d¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (50 mg, rend¡m¡ento del 15 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la A/-fen¡lpentanoam¡da (146 mg, 0,82 mmol) obten¡da en la Etapa 1 del Ejemplo 1 y el metanosulfonato de 3-(4-(p¡r¡d¡n-1-carbon¡l)fen¡l)prop-2-¡n¡lo (396 mg, 1,23 mmol) obten¡do en la Etapa 3.A final product, W-phen¡lW- (3- (4- (p¡per¡d¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide, was obtained (50 mg, 15% yield) by the same method described in Step 5 of Example 1 using A / -phenylpentaneamide (146 mg, 0.82 mmol) obtained in Step 1 of Example 1 and the methanesulfonate of 3- (4- (p¡r¡d¡n-1-carbon¡l) phen¡l) prop-2-¡n¡lo (396 mg, 1.23 mmol) obtained in Step 3.

RMN de 1H (CDCh, 400 MHz) 87,40-7,13 (9H, m), 4,65 (2H, s, CH2), 3,62-3,24 (4H, a), 2,02-1,99 (2H, t), 1,60 (4H, a), 1,52-1,46 (2H, m), 1,44 (2H, a), 1,20-1,08 (2H, m), 0,78-0,73 (3H, t). 1H NMR (CDCh, 400 MHz) 87.40-7.13 (9H, m), 4.65 (2H, s, CH2), 3.62-3.24 (4H, a), 2.02- 1.99 (2H, t), 1.60 (4H, a), 1.52-1.46 (2H, m), 1.44 (2H, a), 1.20-1.08 (2H, m), 0.78-0.73 (3H, t).

Ejemplo 21. Preparación de N,N-d¡et¡l-4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)benzam¡da (LMT-883) Etapa 1: Preparación de 4-bromo-N.N-d¡et¡lbenzam¡daExample 21. Preparation of N, Nd¡et¡l-4- (3- (N-phenylpentaneam¡do) prop-1-¡n¡l) benzam¡da (LMT-883) Step 1: Preparation of 4 -bromo-NN-d¡et¡lbenzam¡da

Se obtuvo 4-bromo-N,N-d¡et¡lbenzam¡da (700 mg, rend¡m¡ento del 69 %) med¡ante el m¡smo método descr¡to en la Etapa 2 del Ejemplo 1 usando ác¡do 4-bromobenzo¡co (800 mg, 3,98 mmol) y d¡et¡lam¡na (0,49 ml, 4,78 mmol). Etapa 2: Preparac¡ón de N.N-d¡et¡l-4-(3-h¡drox¡prop-1-¡n¡l)benzam¡da4-Bromo-N, Nd¡et¡lbenzam¡da (700 mg, yield 69%) was obtained by the same method described in Step 2 of Example 1 using acid 4-bromobenzoic (800 mg, 3.98 mmol) and di-ethylamine (0.49 ml, 4.78 mmol). Step 2: Preparation of N.N-d¡et¡l-4- (3-hydrox¡prop-1-¡n¡l) benzam¡da

Se obtuvo N,N-d¡et¡l-4-(3-h¡drox¡prop-1-¡n¡l)benzam¡da (425 mg, rend¡m¡ento del 67 %) med¡ante el m¡smo método descr¡to en la Etapa 3 del Ejemplo 1 usando la 4-bromo-N,N-d¡et¡lbenzam¡da (700 mg, 2,73 mmol) obten¡da en la Etapa 1 y alcohol propargíl¡co (0,32 ml, 5,47 mmol).N, Nd¡et¡l-4- (3-hydrox¡prop-1-¡n¡l) benzam¡da (425 mg, yield 67%) was obtained by means of the m¡ This method described in Stage 3 of Example 1 using the 4-bromo-N, Nd¡et¡lbenzam¡da (700 mg, 2.73 mmol) obtained in Stage 1 and propargyl alcohol (0 , 32 ml, 5.47 mmol).

Etapa 3: Preparac¡ón de metanosulfonato de 3-(4-(d¡et¡lcarbamo¡l)fen¡l)prop-2-¡n¡loStep 3: Preparation of 3- (4- (d¡etlcarbamo¡l) phen¡l) prop-2-n¡lo methanesulfonate

Se obtuvo metanosulfonato de 3-(4-(d¡et¡lcarbamo¡l)fen¡l)prop-2-¡n¡lo (483 mg, rend¡m¡ento del 85 %) med¡ante el m¡smo método descr¡to en la Etapa 4 del Ejemplo 1 usando la N,N-d¡et¡l-4-(3-h¡drox¡prop-1-¡n¡l)benzam¡da (425 mg, 1,84 mmol) obten¡da en la Etapa 2 y cloruro de metanosulfon¡lo (0,16 ml, 2,02 mmol).3- (4- (d¡et¡carbamo¡l) phen¡l) prop-2-¡n¡lo methanesulfonate (483 mg, 85% yield) was obtained by the same method described in Step 4 of Example 1 using the N, Nd¡et¡l-4- (3-hydrox¡prop-1-¡n¡l) benzamide (425 mg, 1.84 mmol ) obtained in Step 2 and methanesulfonychloride (0.16 ml, 2.02 mmol).

Etapa 4: Preparac¡ón de N.N-d¡et¡l-4-(3-(N-fen¡lpentanam¡do)prop-1-¡n¡l)benzam¡daStep 4: Preparation of N.N-d¡et¡l-4- (3- (N-phenylpentane) prop-1-¡n¡l) benzam¡da

Un producto final, N,N-d¡et¡l-4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)benzam¡da, se obtuvo (81 mg, rend¡m¡ento del 39 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la A/-fen¡lpentanoam¡da (94 mg, 0,530 mmol) obten¡da en la Etapa 1 del Ejemplo 1 y el metanosulfonato de 3-(4-(d¡et¡lcarbamo¡l)fen¡l)prop-2-¡n¡lo (246 mg, 0,795 mmol) obten¡do en la Etapa 3.A final product, N, Nd¡et¡l-4- (3- (N-phenylpentaneamide) prop-1-¡n¡l) benzamide, was obtained (81 mg, yield 39%) by the same method described in Step 5 of Example 1 using the A / -phenylpentaneamide (94 mg, 0.530 mmol) obtained in Step 1 of Example 1 and the 3- (4- (di-ethylcarbamoyl) phenyl) prop-2-ino (246 mg, 0.795 mmol) methanesulfonate obtained in Step 3.

RMN de 1H (CDCla, 400 MHz) 87,48-7,30 (9H, m), 4,73 (2H, s), 3,53-3,23 (4H, a), 2,10-2,07 (2H, t), 1,59-1,57 (2H, m), 1,23-1,10 (8H, m), 0,83-0,80 (3H, t).1H NMR (CDCla, 400 MHz) 87.48-7.30 (9H, m), 4.73 (2H, s), 3.53-3.23 (4H, br), 2.10-2, 07 (2H, t), 1.59-1.57 (2H, m), 1.23-1.10 (8H, m), 0.83-0.80 (3H, t).

Ejemplo 22. Preparac¡ón de N-fen¡l-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-837) Etapa 1: Preparac¡ón de 4-(3-bromobenzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡loExample 22. Preparation of N-phenylN- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (LMT -837) Step 1: Preparation of 4- (3-bromobenzo¡l) p¡peraz¡n-1-carboxylate tert-butyl

Se obtuvo 4-(3-bromobenzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (2,75 g, rend¡m¡ento del 99 %) med¡ante el m¡smo método descr¡to en la Etapa 2 del Ejemplo 1 usando ác¡do 3-bromobenzo¡co (1,50 g, 7,46 mmol) y p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (1,67 g, 8,95 mmol).Ferc-butyl 4- (3-bromobenzol) pi-perazin-1-carboxylate (2.75 g, 99% yield) was obtained by the same method described in Step 2 of Example 1 using 3-bromobenzoic acid (1.50 g, 7.46 mmol) and ferc-butyl pi-perazine-1-carboxylate (1 , 67 g, 8.95 mmol).

Etapa 2: Preparac¡ón de 4-(3-(3-h¡drox¡prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡loStep 2: Preparation of 4- (3- (3-hydrox¡prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate of tert-butyl

Se obtuvo 4-(3-(3-h¡drox¡prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (2,32 g, rend¡m¡ento del 90 %) med¡ante el m¡smo método descr¡to en la Etapa 3 del Ejemplo 1 usando el 4-(3-bromobenzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (2,75 g, 7,45 mmol) obten¡do en la Etapa 1 y alcohol propargíl¡co (0,87 ml, 14,89 mmol).There was obtained ferc-butyl 4- (3- (3-hydrox¡prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate (2.32 g, 90% yield) by the same method described in Step 3 of Example 1 using the 4- (3-bromobenzol) pi-perazin-1-carboxylate tert-butyl (2.75 g, 7.45 mmol) obtained in Step 1 and propargyl alcohol (0.87 ml, 14.89 mmol).

Etapa 3: Preparac¡ón de 4-(3-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡loStep 3: Preparation of 4- (3- (3- (methylsulfon¡lox¡) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate of tert- but¡lo

Se obtuvo 4-(3-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (1,78 g, rend¡m¡ento del 63 %) med¡ante el m¡smo método descr¡to en la Etapa 4 del Ejemplo 1 usando el 4-(3-(3-h¡drox¡prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (2,32 g, 6,75 mmol) obten¡do en la Etapa 2 y cloruro de metanosulfon¡lo (0,58 ml, 7,42 mmol).There was obtained 4- (3- (3- (methsulfon¡lox¡) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate of ferc-butyl (1 , 78 g, 63% yield) by the same method described in Step 4 of Example 1 using the 4- (3- (3-hydrox¡prop-1-¡ n¡l) benzo¡l) p¡peraz¡n-1-carboxylate of ferc-butyl (2.32 g, 6.75 mmol) obtained in Step 2 and methanesulfonyl chloride ( 0.58 ml, 7.42 mmol).

Etapa 4: Preparac¡ón de 4-(3-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo Un producto f¡nal, 4-(3-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo, se obtuvo (323 mg, rend¡m¡ento del 70 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la N-fen¡lpentanoam¡da (275 mg, 1,55 mmol) obten¡da en la Etapa 1 del Ejemplo 1 y el 4-(3-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (982 mg, 2,33 mmol) obten¡do en la Etapa 3.Step 4: Preparation of 4- (3- (3- (N-phenylpentaneamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate of tert -but¡lo A final product, 4- (3- (3- (N-phenylpentaneamido) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carbox¡ ferc-butyllate, (323 mg, yield 70%) was obtained by the same method described in Step 5 of Example 1 using the N- phenylpentaneamide (275 mg, 1.55 mmol) obtained in Step 1 of Example 1 and the 4- (3- (3- (methylsulfon¡lox¡) prop-1-¡n¡l) benzo¡l) tert-butyl piperazin-1-carboxylate (982 mg, 2.33 mmol) obtained in Step 3.

Etapa 5: Preparac¡ón de N-fen¡l-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-837)Step 5: Preparation of N-phen¡lN- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (LMT -837)

Un producto f¡nal, N-fen¡l-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (152 mg, rend¡m¡ento del 58 %) med¡ante el m¡smo método descr¡to en el Ejemplo 2 usando el 4-(3-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (323 mg, 0,62 mmol) obten¡do en la Etapa 4.A final product, N-phenylN- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide, was obtained (152 mg, 58% yield) by the same method described in Example 2 using the 4- (3- (3- (N-phenylpentane) prop-1 -¡N¡l) benzo¡l) p¡peraz¡n-1-carboxylate of ferc-butyl (323 mg, 0.62 mmol) obtained in Step 4.

RMN de 1H (CDCla, 400 MHz) 87,45-7,26 (9H, m), 4,69 (2H, s), 3,75-3,36 (4H, a), 2,94-2,80 (4H, a), 2,59 (1H, a), 2,07-2,04 (2H, t), 1,56-1,53 (2H, m), 1,22-1,18 (2H, m), 0,80-0,77 (3H, t). 1H NMR (CDCla, 400 MHz) 87.45-7.26 (9H, m), 4.69 (2H, s), 3.75-3.36 (4H, a), 2.94-2, 80 (4H, a), 2.59 (1H, a), 2.07-2.04 (2H, t), 1.56-1.53 (2H, m), 1.22-1.18 ( 2H, m), 0.80-0.77 (3H, t).

Ejemplo 23. Preparación de N-(3-(3-(4-met¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (LMT-838) La N-fen¡l-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (50 mg, 0,124 mmol) obtenida en el Ejemplo 22 y formaldehído (37 % en H2O; 1,5 ml) se d¡solv¡eron en ác¡do fórm¡co (2,0 ml), se calentaron a 100 °C, se somet¡eron a reflujo y se ag¡taron durante 4 horas. La soluc¡ón de reacc¡ón se concentró a pres¡ón reduc¡da y se valoró med¡ante la ad¡c¡ón de una soluc¡ón acuosa de h¡dróx¡do de sod¡o (2,0 M). Después, el producto de reacc¡ón se d¡luyó con d¡clorometano y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (CH2Cl2:MeOH=20 :1 ), obten¡endo de este modo N-(3-(3-(4-met¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (24 mg, rend¡m¡ento del 46 %). RMN de 1H (CDCla, 400 MHz) 87,46-7,29 (9H, m), 4,70 (2H, s), 3,79-3,39 (4H, a), 2,48-2,32 (7H, a), 2,08-2,05 (2H, t), 1,57-1,54 (2H, m), 1,23-1,19 (2H, m), 0,81-0,78 (3H, t).Example 23. Preparation of N- (3- (3- (4-methylp¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-phenylpentaneam¡ gives (LMT-838) N-phen¡lN- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (50 mg, 0.124 mmol) obtained in Example 22 and formaldehyde (37% in H2O; 1.5 ml) were dissolved in formic acid (2.0 ml), heated to 100 ° C, they were refluxed and stirred for 4 hours. The reaction solution was concentrated under reduced pressure and titrated by adding an aqueous solution of sodium hydroxide (2.0 M ). The reaction product was then diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Cl2: MeOH = 20: 1), thereby obtaining N- (3- (3- (4-methylp ¡Peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-phenylpentaneamide (24 mg, yield 46%). 1H NMR (CDCla, 400 MHz) 87.46-7.29 (9H, m), 4.70 (2H, s), 3.79-3.39 (4H, a), 2.48-2, 32 (7H, a), 2.08-2.05 (2H, t), 1.57-1.54 (2H, m), 1.23-1.19 (2H, m), 0.81- 0.78 (3H, t).

Ejemplo 24. Preparac¡ón de N-(3-(3-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (LMT-842) Un producto f¡nal, A/-(3-(3-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)-A/-fen¡lpentanoam¡da, se obtuvo (67 mg, rend¡m¡ento del 40 %) med¡ante el m¡smo método descr¡to en el Ejemplo 5 usando la N-fen¡l-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (152 mg, 0,36 mmol) obten¡da en el Ejemplo 22 y 2-yodopropano (90 pl, 0,90 mmol).Example 24. Preparation of N- (3- (3- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) -N-fen ¡Lpentanoam¡da (LMT-842) A final product, A / - (3- (3- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2- N¡l) -A / -phenylpentaneamide, (67 mg, 40% yield) was obtained by the same method described in Example 5 using the N-phen ¡LN- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (152 mg, 0.36 mmol) obtained in Example 22 and 2-iodopropane (90 µl, 0.90 mmol).

RMN de 1H (CDCla, 400 MHz) 87,47-7,29 (9H, m), 4,71 (2H, s), 3,79-3,40 (4H, a), 2,78-2,75 (1H, m), 2,60-2,46 (4H, a), 2,09-2,06 (2H, t), 1,58-1,55 (2H, m), 1,24-1,20 (2H, m), 1,07-1,05 (6H, d), 0,82-0,79 (3H, t).1H NMR (CDCla, 400 MHz) 87.47-7.29 (9H, m), 4.71 (2H, s), 3.79-3.40 (4H, a), 2.78-2, 75 (1H, m), 2.60-2.46 (4H, a), 2.09-2.06 (2H, t), 1.58-1.55 (2H, m), 1.24- 1.20 (2H, m), 1.07-1.05 (6H, d), 0.82-0.79 (3H, t).

Ejemplo 25. Preparac¡ón de 4-(3-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (LMT-887)Example 25. Preparation of 4- (3- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1- tert- butyl carboxylate (LMT-887)

Un producto f¡nal, 4-(3-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo, se obtuvo (625 mg, rend¡m¡ento del 85 %) med¡ante el m¡smo método descr¡to en la Etapa 5 del Ejemplo 1 usando la N-(4-fluorofen¡l)pentanoam¡da (275 mg, 1,41 mmol) obten¡da en la Etapa 1 del Ejemplo 16 y el 4-(3-(3-(met¡lsulfon¡lox¡)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (894 mg, 2,12 mmol) obten¡do en la Etapa 3 del Ejemplo 22.An end product, 4- (3- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carbox Tert-butyllate, (625 mg, 85% yield) was obtained by the same method described in Step 5 of Example 1 using the N- (4-fluorophen ¡L) pentanoamide (275 mg, 1.41 mmol) obtained in Step 1 of Example 16 and the 4- (3- (3- (methysulfon¡lox¡) prop-1-¡n¡ l) benzoyl) pi-perazin-1-carboxylate tert-butyl (894 mg, 2.12 mmol) obtained in Step 3 of Example 22.

RMN de 1H (CDCh, 400 MHz) 87,33-7,20 (6H, m), 7,09-7,06 (2H, m), 4,62 (2H, s), 3,66-3,31 (8H, a), 2,00-1,97 (2H, t), 1,52-1,49 (2H, m), 1,47 (9H, s), 1,18-1,13 (2H, m), 0,76-0,73 (3H, t).1H NMR (CDCh, 400 MHz) 87.33-7.20 (6H, m), 7.09-7.06 (2H, m), 4.62 (2H, s), 3.66-3, 31 (8H, a), 2.00-1.97 (2H, t), 1.52-1.49 (2H, m), 1.47 (9H, s), 1.18-1.13 ( 2H, m), 0.76-0.73 (3H, t).

Ejemplo 26. Preparac¡ón de N-(4-fluorofen¡l)-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-888) Un producto f¡nal, N-(4-fluorofen¡l)-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (356 mg, rend¡m¡ento del 58 %) med¡ante el m¡smo método descr¡to en el Ejemplo 2 usando el 4-(3-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)benzo¡l)p¡peraz¡n-1-carbox¡lato de terc-but¡lo (762 mg, 1,46 mmol) obten¡do en el Ejemplo 25.Example 26. Preparation of N- (4-fluorophenyl) -N- (3- (3- (p¡peraz¡n-1-carbon¡l) phenl) prop-2-¡n¡l ) Pentanoamide (LMT-888) A final product, N- (4-fluorophenyl) -N- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide, (356 mg, 58% yield) was obtained by the same method described in Example 2 using the 4- (3- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-¡n¡l) benzo¡l) p¡peraz¡n-1-carboxylate tert-butyl (762 mg , 1.46 mmol) obtained in Example 25.

RMN de 1H (CDCls, 400 MHz) 87,39-7,29 (6H, m), 7,17-7,14 (2H, m), 4,70 (2H, s), 3,77-3,39 (4H, a), 2,98-2,85 (4H, a), 2,08-2,05 (2H, t), 1,60-1,54 (2H, m), 1,25-1,19 (2H, m), 0,84-0,81 (3H, t).1H NMR (CDCls, 400 MHz) 87.39-7.29 (6H, m), 7.17-7.14 (2H, m), 4.70 (2H, s), 3.77-3, 39 (4H, a), 2.98-2.85 (4H, a), 2.08-2.05 (2H, t), 1.60-1.54 (2H, m), 1.25- 1.19 (2H, m), 0.84-0.81 (3H, t).

Ejemplo 27. Preparac¡ón de N-(4-fluorofen¡l)-N-(3-(3-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (LMT-889)Example 27. Preparation of N- (4-fluorophenyl) -N- (3- (3- (4-isopropylp¡peraz¡n-1-carbon¡l) phen¡l) prop-2 -¡N¡l) pentanoam¡da (LMT-889)

Un producto f¡nal, N-(4-fluorofen¡l)-N-(3-(3-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da, se obtuvo (66 mg, rend¡m¡ento del 40 %) med¡ante el m¡smo método descr¡to en el Ejemplo 5 usando la N-(4-fluorofen¡l)-N-(3-(3-(p¡peraz¡n-1-carbon¡l)fen¡l)prop-2-¡n¡l)pentanoam¡da (150 mg, 0,356 mmol) obten¡da en el Ejemplo 26 y 2-yodopropano (53 pl, 0,534 mmol).A final product, N- (4-fluorophenyl) -N- (3- (3- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) phen¡l) prop-2- N¡l) pentanoamide, (66 mg, yield 40%) was obtained by the same method described in Example 5 using the N- (4-fluorophenil) -N- (3- (3- (p¡peraz¡n-1-carbon¡l) phen¡l) prop-2-¡n¡l) pentanoamide (150 mg, 0.356 mmol) obtained in the Example 26 and 2-iodopropane (53 µl, 0.534 mmol).

RMN de 1H (CDCls, 400 MHz) 87,37-7,29 (6H, m), 7,16-7,13 (2H, m), 4,70 (2H, s), 3,79-3,39 (4H, a), 2,75-2,73 (1H, m), 2,59-2,45 (4H, a), 2,07-2,04 (2H, t), 1,58-1,55 (2H, m), 1,25-1,21 (2H, m), 1,06-1,05 (6H, d), 0,84-0,81 (3H, t). Ejemplo 28. Preparac¡ón de N-(3-(4-h¡drox¡fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (LMT-890)1H NMR (CDCls, 400 MHz) 87.37-7.29 (6H, m), 7.16-7.13 (2H, m), 4.70 (2H, s), 3.79-3, 39 (4H, a), 2.75-2.73 (1H, m), 2.59-2.45 (4H, a), 2.07-2.04 (2H, t), 1.58- 1.55 (2H, m), 1.25-1.21 (2H, m), 1.06-1.05 (6H, d), 0.84-0.81 (3H, t). Example 28. Preparation of N- (3- (4-hydroxyphenil) prop-2-nil) -N- phenylpentaneamide (LMT-890)

Etapa 1: Preparac¡ón de N-(prop-2-¡n¡l)an¡l¡naStage 1: Preparation of N- (prop-2-¡n¡l) an¡l¡na

Se d¡solv¡eron an¡l¡na (2,94 ml, 32,21 mmol) y carbonato de potas¡o (4,90 g, 35,43 mmol) en aceton¡tr¡lo (40 ml) y la mezcla se ag¡tó durante 5 m¡nutos. Se añad¡ó bromuro de proparg¡lo (3,05 ml, 35,43 mmol) a la mezcla y la mezcla se ag¡tó a temperatura amb¡ente durante 17 horas. La soluc¡ón de reacc¡ón se f¡ltró para ret¡rar un sól¡do y se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex), obten¡endo de este modo N-(prop-2-¡n¡l)an¡l¡na (2,23 g, rend¡m¡ento del 53 %).Aniline (2.94 ml, 32.21 mmol) and potassium carbonate (4.90 g, 35.43 mmol) were dissolved in acetonitrile (40 ml) and The mixture was stirred for 5 minutes. Propargyl bromide (3.05 ml, 35.43 mmol) was added to the mixture and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered to remove a solid and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (Hex), thereby obtaining N- (prop-2-¡n¡l) an¡na (2, 23 g, 53% yield).

Etapa 2: Preparac¡ón de N-fen¡l-N-(prop-2-¡n¡l)pentanoam¡daStage 2: Preparation of N-phenl-N- (prop-2-nl) pentanoamide

Se obtuvo N-fen¡l-N-(prop-2-¡n¡l)pentanoam¡da (1,29 g, rend¡m¡ento del 95 %) med¡ante el m¡smo método descr¡to en la Etapa 1 del Ejemplo 1 usando la N-(prop-2-¡n¡l)an¡l¡na (828 mg, 6,31 mmol) obten¡da en la Etapa 1 y cloruro de valeroílo (1,53 ml, 12,62 mmol).N-phenylN- (prop-2-¡n¡l) pentanoamide (1.29 g, 95% yield) was obtained by the same method described in Step 1 of Example 1 using the N- (prop-2-¡n¡l) an¡na (828 mg, 6.31 mmol) obtained in Step 1 and Valeroyl (1.53 ml, 12.62 mmol).

Etapa 3: Preparación de A/-(3-(4-h¡drox¡fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡daStep 3: Preparation of A / - (3- (4-hydroxyphenyl) prop-2-¡n¡l) -N-phenylpentaneam¡da

La A/-fen¡l-W-(prop-2-¡n¡l)pentanoam¡da (550 mg, 2,55 mmol) obten¡da en la Etapa 2 y 4-yodofenol (422 mg, 1,92 mmol) se d¡solv¡eron en tr¡et¡lam¡na (15 ml) y la mezcla se ag¡tó durante 5 m¡nutos. Se añad¡eron d¡cloruro de b¡s(tr¡fen¡lfosf¡na)palad¡o (II) (89 mg, 0128 mmol) y yoduro de cobre (I) (49 mg, 0,255 mmol) a la mezcla, la mezcla se calentó a 50 °C, se somet¡ó a reflujo y se ag¡tó durante 5 horas. La soluc¡ón de reacc¡ón se enfr¡ó a temperatura amb¡ente y se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex:EA=10:1), obten¡endo de este modo un producto f¡nal, A/-(3-(4-h¡drox¡fen¡l)prop-2-¡n¡l)-W-fen¡lpentanoam¡da (590 mg, rend¡m¡ento del 75 %).The A / -phenylW- (prop-2-¡n¡l) pentanoamide (550 mg, 2.55 mmol) obtained in Step 2 and 4-iodophenol (422 mg, 1.92 mmol) They were dissolved in trietlamine (15 ml) and the mixture was stirred for 5 minutes. Bis (triphenylphosphine) palladium (II) dichloride (89 mg, 0128 mmol) and copper (I) iodide (49 mg, 0.255 mmol) were added to the mixture , the mixture was heated to 50 ° C, refluxed and stirred for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate and washed with water. and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 10: 1), thus obtaining a final product, A / - (3- (4 -h¡drox¡fen¡l) prop-2-¡n¡l) -W-phenylpentaneamida (590 mg, 75% yield).

RMN de 1H (CDCl3, 400 MHz) 88,15 (1H, a), 7,47-6,83 (9H, m), 4,66 (2H, s), 2,13-2,10 (2H, t), 1,60-1,54 (2H, m), 1.22- 1,17 (2H, m), 0,80-0,77 (3H, t).1H NMR (CDCl3, 400 MHz) 88.15 (1H, br), 7.47-6.83 (9H, m), 4.66 (2H, s), 2.13-2.10 (2H, t), 1.60-1.54 (2H, m), 1.22-1.17 (2H, m), 0.80-0.77 (3H, t).

Ejemplo 29. Preparac¡ón de ác¡do 2-(4-(3-(A/-fen¡lpentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡co (LMT-891)Example 29. Preparation of 2- (4- (3- (A / -phenylpentaneamide) prop-1-inl) phenoxy) acetic acid (LMT-891)

Etapa 1: Preparac¡ón de (2-(4-(3-(A/-fen¡lpentanoam¡do)prop-1-¡n¡l)fenox¡)acetato de etiloStep 1: Preparation of ethyl (2- (4- (3- (A / -phenylpentane) prop-1-¡n¡l) phenox¡) acetate

La W-(3-(4-h¡drox¡fen¡l)prop-2-¡n¡l)-A/-fen¡lpentanoam¡da (590 mg, 1,92 mmol) obten¡da en el Ejemplo 28 y carbonato de potas¡o (796 mg, 5,76 mmol) se d¡solv¡eron en aceton¡tr¡lo (15 ml) y la mezcla se ag¡tó durante 30 m¡nutos. Se añad¡ó bromoacetato de et¡lo (0,23 ml, 2,11 mmol) a la mezcla y la mezcla se ag¡tó a temperatura amb¡ente durante 17 horas. La soluc¡ón de reacc¡ón se f¡ltró para ret¡rar un sól¡do y se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex:EA=10:1), obten¡endo de este modo 2-(4-(3-(A/-fen¡lpentanoam¡do)prop-1-¡n¡l)fenox¡)acetato de et¡lo (530 mg, rend¡m¡ento del 70 %).The W- (3- (4-hydroxyphenyl) prop-2-¡n¡l) -A / -phenylpentaneamide (590 mg, 1.92 mmol) obtained in Example 28 and potassium carbonate (796 mg, 5.76 mmol) were dissolved in acetonitrile (15 ml) and the mixture was stirred for 30 minutes. Ethyl bromoacetate (0.23 ml, 2.11 mmol) was added to the mixture and the mixture was stirred at room temperature for 17 hours. The reaction solution was filtered to remove a solid and concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 10: 1), thus obtaining 2- (4- (3- (A / -fen¡ Ethyl pentane (530 mg, 70% yield).

Etapa 2: Preparac¡ón de ác¡do 2-(4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡coStep 2: Preparation of 2- (4- (3- (N-phenylpentanoamide) prop-1-¡n¡l) phenox¡) acetic acid

El 2-(4-(3-(A/-fen¡lpentanoam¡do)prop-1-¡n¡l)fenox¡)acetato de et¡lo (530 mg, 1,35 mmol) obten¡do en la Etapa 1 se d¡solv¡ó en etanol (15 ml) y la mezcla se ag¡tó a temperatura amb¡ente durante 5 m¡nutos. Se añad¡ó h¡dróx¡do de sod¡o 2 N (NaOH; 0,50 ml) a la mezcla, la mezcla se calentó a 80 °C, se somet¡ó a reflujo y se ag¡tó durante 3 horas. La soluc¡ón de reacc¡ón se enfr¡ó a temperatura amb¡ente y se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (CH2Cl2:MeOH=100 :1 ), obten¡endo de este modo un producto f¡nal, ác¡do 2-(4-(3-(W-fen¡lpentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡co (246 mg, rend¡m¡ento del 50 %).The 2- (4- (3- (A / -phenylpentaneamide) prop-1-¡n¡l) phenoxy) ethyl acetate (530 mg, 1.35 mmol) obtained in the Step 1 was dissolved in ethanol (15 ml) and the mixture was stirred at room temperature for 5 minutes. 2N sodium hydroxide (NaOH; 0.50 ml) was added to the mixture, the mixture was heated to 80 ° C, refluxed and stirred for 3 hours . The reaction solution was cooled to room temperature and concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate and washed with water. and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (CH2Cl2: MeOH = 100: 1), thus obtaining a final product, acid 2- (4- (3- (W-phenylpentaneamido) prop-1-¡n¡l) phenox¡) acetic (246 mg, 50% yield).

RMN de 1H (CDCla, 400 MHz) 87,47-6,78 (9H, m), 4,68 (2H, s), 4,58 (2H, s), 2,11-2,08 (2H, t), 1,58-1,53 (2H, m), 1.23- 1,18 (2H, m), 0,81-0,78 (3H, t).1H NMR (CDCla, 400 MHz) 87.47-6.78 (9H, m), 4.68 (2H, s), 4.58 (2H, s), 2.11-2.08 (2H, t), 1.58-1.53 (2H, m), 1.23-1.18 (2H, m), 0.81-0.78 (3H, t).

Ejemplo 30. Preparac¡ón de 4-(5-(3-(W-fen¡lpentanam¡do)prop-1-¡n-1-¡l)p¡col¡no¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (LMT-834)Example 30. Preparation of 4- (5- (3- (W-phenylpentane) prop-1-¡n-1-¡l) p¡col¡no¡l) p¡peraz¡n- Ferc-butylo 1-carboxylate (LMT-834)

Un producto f¡nal, 4-(5-(3-(W-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)p¡col¡no¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo, (36 mg, rend¡m¡ento del 35 %) se obtuvo usando el m¡smo método descr¡to en la Etapa 3 del Ejemplo 28 usando la W-fen¡l-W-(prop-2-¡n¡l)pentanoam¡da obten¡da en la Etapa 2 del Ejemplo 28 y 4-(5-bromop¡col¡no¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (86 mg, 0,4 mmol).An end product, 4- (5- (3- (W-phenylpentaneamide) prop-1-¡n-1-¡l) p¡col¡no¡l) p¡peraz¡n-1 Ferc-butyl carboxylate, (36 mg, 35% yield) was obtained using the same method described in Step 3 of Example 28 using the W-phenylW- (prop-2-¡n¡l) pentanoam¡da obtained in Step 2 of Example 28 and 4- (5-bromop¡col¡no¡l) p¡peraz¡n-1-carboxylate from ferc -butyl (86 mg, 0.4 mmol).

RMN de 1H (400 MHz, CDCla) 88,43 (s, 1H), 7,64 (dd, 1H), 7,54 (dd, 1H), 7,36 (dd, 3H), 7,18 (m, 2H), 4,68 (s, 2H), 3.69 (a, 2H), 3,53-3,38 (a, 6H), 2,01 (m, 2H), 1,52 (m, 2H), 1,39 (s, 9H), 1,18 (m, 2H), 0,73 (t, 3H).1H NMR (400MHz, CDCla) 88.43 (s, 1H), 7.64 (dd, 1H), 7.54 (dd, 1H), 7.36 (dd, 3H), 7.18 (m , 2H), 4.68 (s, 2H), 3.69 (a, 2H), 3.53-3.38 (a, 6H), 2.01 (m, 2H), 1.52 (m, 2H) , 1.39 (s, 9H), 1.18 (m, 2H), 0.73 (t, 3H).

Ejemplo 31. Preparac¡ón de W-fen¡l-W-(3-(6-(p¡peraz¡n-1-carbon¡l)p¡r¡d¡n-3-¡l)prop-2-¡n-1-¡l)pentanoam¡da (LMT-835) El 4-(5-(3-((W-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)p¡col¡no¡l)p¡peraz¡n-1-carbox¡lato de ferc-but¡lo (35 mg, 0,69 mmol) obten¡do en el Ejemplo 30 se d¡solv¡ó en aceton¡tr¡lo (15 ml) y la mezcla se ag¡tó a temperatura amb¡ente durante 5 m¡nutos. Se añad¡ó clorh¡drato m¡xto de d¡oxano (4 N; 3,73 ml) a la mezcla, y la mezcla se ag¡tó a la m¡sma temperatura durante 1,5 horas. La soluc¡ón de reacc¡ón se concentró a pres¡ón reduc¡da, y el res¡duo obten¡do se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (CH2Ch:MeOH=50:1), obten¡endo de este modo un producto f¡nal, A/-fen¡l-A/-(3-(6-(p¡peraz¡n-1-carbon¡l)p¡r¡d¡n-3-¡l)prop-2-¡n-1-¡l)pentanoam¡da (18 mg, rend¡m¡ento del 64 %).Example 31. Preparation of W-phen¡lW- (3- (6- (p¡peraz¡n-1-carbon¡l) p¡r¡d¡n-3-¡l) prop-2-¡ n-1-¡l) pentanoam¡da (LMT-835) The 4- (5- (3 - ((W-phenylpentanoam¡do) prop-1-¡n-1-¡l) p¡col¡ no¡l) p¡peraz¡n-1-carboxylate of ferc-butyl (35 mg, 0.69 mmol) obtained in Example 30 was dissolved in acetonitrile ( 15 ml) and the mixture was stirred at room temperature for 5 minutes, mixed dixane hydrochloride (4 N; 3.73 ml) was added to the mixture, and The mixture was stirred at the same temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by means of Before column chromatography on silica gel (CH2Ch: MeOH = 50: 1), thus obtaining a final product, A / -pheneA / - (3- (6- (p¡ peraz¡n-1-carbon¡l) p¡r¡d¡n-3-¡l) prop-2-¡n-1-¡l) pentanoam¡da (18 mg, 64% yield ).

RMN de 1H (400 MHz, CDCls) 88,43 (s, 1H), 7,66 (dd, 1H), 7,49 (dd, 1H), 7,36 (dd, 3H), 7,21 (m, 2H), 4,67 (s, 2H), 3.70 (a, 2H), 3,48 (a, 2H), 2,90 (a, 2H), 2,81 (a, 2H), 2,01 (m, 2H), 1,49 (m, 2H), 1,17 (m, 2H), 0,73 (t, 3H).1H NMR (400 MHz, CDCls) 88.43 (s, 1H), 7.66 (dd, 1H), 7.49 (dd, 1H), 7.36 (dd, 3H), 7.21 (m , 2H), 4.67 (s, 2H), 3.70 (a, 2H), 3.48 (a, 2H), 2.90 (a, 2H), 2.81 (a, 2H), 2.01 (m, 2H), 1.49 (m, 2H), 1.17 (m, 2H), 0.73 (t, 3H).

Ejemplo 32. Preparac¡ón de W-(3-(6-(4-¡soprop¡lp¡peraz¡n-1-carbon¡l)p¡r¡d¡n-3-¡l)prop-2-¡n-1-¡l)-A/-fen¡lpentanoam¡da (LMT-836) Example 32. Preparation of W- (3- (6- (4-¡soprop¡lp¡peraz¡n-1-carbon¡l) p¡r¡d¡n-3-¡l) prop-2- ¡N-1-¡l) -A / -phenylpentaneamide (LMT-836)

La A/-fen¡l-A/-(3-(6-(p¡peraz¡n-1-carbon¡l)p¡rid¡n-3-¡l)prop-2-¡n-1-¡l)pentanoam¡da (57,7 mg, 0,14 mmol) obtenida en el Ejemplo 31 y bicarbonato de sodio (27 mg, 0,316 mmol) se enfriaron en hielo y se añadió A/,W-dimet¡lformamida (DMF; 2 ml), seguido de agitación durante 1 hora. Se añadió 2-yodopropano (30 pl, 0,316 mmol) a la mezcla, el hielo se retiró y el producto resultante se calentó a 60 °C, se sometió a reflujo y se agitó durante 24 horas. La solución de reacción se enfrió a temperatura ambiente y se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA:MeOH:TEA=12:12:1:0,1), obteniendo de este modo un producto final, W-(3-(6-¡soprop¡lp¡peraz¡n-1-carbon¡l)p¡r¡din-3-¡l)prop-2-¡n-1-¡l)-A/-fen¡lpentanoam¡da (32,3 mg, rendimiento del 51 %).The A / -fen¡lA / - (3- (6- (p¡peraz¡n-1-carbon¡l) p¡rid¡n-3-¡l) prop-2-¡n-1-¡l ) Pentanoamide (57.7 mg, 0.14 mmol) obtained in Example 31 and sodium bicarbonate (27 mg, 0.316 mmol) were cooled on ice and A / W-dimethylformamide (DMF; 2) was added ml), followed by stirring for 1 hour. 2-Iodopropane (30 µl, 0.316 mmol) was added to the mixture, the ice was removed and the resulting product was heated to 60 ° C, refluxed and stirred for 24 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA: MeOH: TEA = 12: 12: 1: 0.1), thereby obtaining a final product, W- (3- (6-isoprop ¡Lp¡peraz¡n-1-carbon¡l) p¡r¡din-3-¡l) prop-2-¡n-1-¡l) -A / -phenylpentaneam¡da (32.3 mg , 51% yield).

RMN de 1H (400 MHz, CDCla) 88,44 (s, 1H), 7,65 (dd, 1H), 7,51 (dd, 1H), 7,39 (dd, 3H), 7,22 (m, 2H), 4,68 (s, 2H), 3,74 (a, 2H), 3,52 (a, 2H), 2,67 (m, 1H), 2,55 (a, 2H), 2,41 (a, 2H), 2,02 (m, 2H), 1,50 (m, 2H), 1,15 (m, 2H), 0,98 (d, 6H), 0,74 (t, 3H).1H NMR (400MHz, CDCla) 88.44 (s, 1H), 7.65 (dd, 1H), 7.51 (dd, 1H), 7.39 (dd, 3H), 7.22 (m , 2H), 4.68 (s, 2H), 3.74 (a, 2H), 3.52 (a, 2H), 2.67 (m, 1H), 2.55 (a, 2H), 2 , 41 (br, 2H), 2.02 (m, 2H), 1.50 (m, 2H), 1.15 (m, 2H), 0.98 (d, 6H), 0.74 (t, 3H).

Ejemplo 33. Preparación de W,A/-d¡et¡l-4-(3-(W-(3-fluorofenil)pentanoam¡do)prop-1-¡n-1-¡l)benzam¡da (LMT-926) Example 33. Preparation of W, A / -d¡et¡l-4- (3- (W- (3-fluorophenyl) pentanoamide) prop-1-¡n-1-¡l) benzamide (LMT -926)

Etapa 1: Preparación de 4-bromo-A/.N-diet¡lbenzam¡daStep 1: Preparation of 4-bromo-A / .N-diet¡lbenzam¡da

Se disolvió ácido 4-bromobenzoico (5,00 g, 24,9 mmol) en A/,W-dimet¡lformamida (100,00 ml) y se mezcló con diisopropilamina (13 ml, 74,6 mmol). Se añadieron hidrato de 1-hidroxibenzotriazol (7,15 mg, 37,30 mmol) y clorhidrato de 1-etil-3-(3-d¡met¡lam¡noprop¡l)carbod¡¡mida (5,04 mg, 37,30 mmol) a la mezcla y la mezcla se agitó durante 5 minutos. Se añadió dietilamina (3,1 ml, 37,3 mmol) a la mezcla y la mezcla se agitó a temperatura ambiente durante 12 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=3:1), obteniendo de este modo 4-bromo-W,W-dietilbenzamida (5,70 g, rendimiento del 89 %).4-Bromobenzoic acid (5.00 g, 24.9 mmol) was dissolved in A / W-dimethylformamide (100.00 ml) and diisopropylamine (13 ml, 74.6 mmol) was added. 1-Hydroxybenzotriazole hydrate (7.15 mg, 37.30 mmol) and 1-ethyl-3- (3-dimethylamnopropyl) carbodimide hydrochloride (5.04 mg, 37.30 mmol) to the mixture and the mixture was stirred for 5 minutes. Diethylamine (3.1 ml, 37.3 mmol) was added to the mixture and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 3: 1), thereby obtaining 4-bromo-W, W-diethylbenzamide (5.70 g, 89% yield).

Etapa 2: Preparación de A/.N-d¡et¡l-4-(3-h¡drox¡prop-1-in¡l)benzam¡daStep 2: Preparation of A / .N-d¡et¡l-4- (3-hydrox¡prop-1-yl) benzam¡da

La 4-bromo-W,A/-dietilbenzam¡da (5,70 mg, 22,3 mmol) obtenida en la Etapa 1 y alcohol propargílico (2,60 ml, 44,5 mmol) se disolvieron en trietilamina (100,00 ml) y la mezcla se agitó durante 5 minutos. Se añadieron dicloruro de bis(trifen¡lfosf¡na)palad¡o (II) (1,60 mg, 2,23 mmol) y yoduro de cobre (I) (1,60 mg, 2,23 mmol) a la mezcla, la mezcla se calentó a 60 °C, se sometió a reflujo y se agitó durante 17 horas. La solución de reacción se enfrió a temperatura ambiente, se concentró a presión reducida, y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=1:1), obteniendo de este modo W,A/-diet¡l-4-(3-h¡drox¡prop-1-¡n¡l)benzam¡da (5,16 mg, rendimiento del 99,9 %).The 4-bromo-W, A / -diethylbenzamide (5.70 mg, 22.3 mmol) obtained in Step 1 and propargyl alcohol (2.60 ml, 44.5 mmol) were dissolved in triethylamine (100, 00 ml) and the mixture was stirred for 5 minutes. Bis (triphenylphosphine) palladium (II) dichloride (1.60 mg, 2.23 mmol) and copper (I) iodide (1.60 mg, 2.23 mmol) were added to the mixture , the mixture was heated to 60 ° C, refluxed and stirred for 17 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 1: 1), thereby obtaining W, A / -dietl-4- (3-hydroxyprop-1-n L) benzamide (5.16 mg, 99.9% yield).

Etapa 3: Preparación de metanosulfonato de 3-(4-(diet¡lcarbamo¡l)fen¡l)prop-2-¡n-1-¡loStep 3: Preparation of 3- (4- (diethylcarbamoyl) phenyl) prop-2-¡n-1-¡lo methanesulfonate

Se disolvió W,A/-d¡etil-4-(3-h¡drox¡prop-1-¡n¡l)benzam¡da (5,16 mg, 22,3 mmol) en diclorometano (100 ml) y la mezcla se enfrió en hielo. Se añadió trietilamina (4,80 ml, 34,4 mmol) a la mezcla y la mezcla se agitó durante 5 minutos. Se añadió cloruro de metanosulfonilo (1,95 ml, 25,2 mmol) a la misma temperatura, el hielo se retiró y la mezcla se agitó a temperatura ambiente durante 30 minutos. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=2:1), obteniendo de este modo metanosulfonato de 3-(4-(dietilcarbamoil)fenil)prop-2-in-1-ilo (4,2 mg, rendimiento del 59 %).W, A / -d¡ethyl-4- (3-hydrox¡prop-1-¡n¡l) benzamide (5.16 mg, 22.3 mmol) was dissolved in dichloromethane (100 ml) and the mixture was cooled on ice. Triethylamine (4.80 ml, 34.4 mmol) was added to the mixture and the mixture was stirred for 5 minutes. Methanesulfonyl chloride (1.95 ml, 25.2 mmol) was added at the same temperature, the ice was removed and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 2: 1), thereby obtaining 3- (4- (diethylcarbamoyl) phenyl) prop-2-yn-1-yl (4, 2 mg, 59% yield).

Etapa 4: Preparación de A/.N-d¡et¡l-4-(3-(N-(3-fluorofen¡l)pentanoam¡do)prop-1-in-1-¡l)benzam¡daStep 4: Preparation of A / .N-di-ethyl-4- (3- (N- (3-fluorophenyl) pentanoamide) prop-1-in-1-¡l) benzamide

Se disolvió W-(3-fluorofenil)pentanoamida (200 mg, 1,02 mmol) en tetrahidrofurano (10,00 ml) y la mezcla se enfrió en hielo. Se añadió hidróxido de sodio (73 mg, 3,06 mmol) a la mezcla y la mezcla se agitó durante 1 hora. El 3-(4-(W,W-diet¡lcarbamo¡l)fenil)prop-2-¡n¡l metanosulfonato (475 mg, 1,54 mmol) obtenido en la Etapa 3 se añadió a la misma temperatura y la mezcla se agitó a temperatura ambiente durante 4 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con diclorometano y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex: EA=2:1), obteniendo de este modo W,W-diet¡l-4-(3-(A/-(3-fluorofen¡l)pentanoamido)prop-1-¡n-1-il)benzamida (291,7 mg, rendimiento del 70 %).W- (3-fluorophenyl) pentanoamide (200mg, 1.02mmol) was dissolved in tetrahydrofuran (10.00ml) and the mixture cooled on ice. Sodium hydroxide (73 mg, 3.06 mmol) was added to the mixture and the mixture was stirred for 1 hour. The 3- (4- (W, W-diethylcarbamoyl) phenyl) prop-2-inl methanesulfonate (475 mg, 1.54 mmol) obtained in Step 3 was added at the same temperature and the The mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 2: 1), thereby obtaining W, W-diethyl-4- (3- (A / - (3-fluorophenil) pentanoamido) prop-1-in-1-yl) benzamide (291.7 mg, 70% yield).

RMN de 1H (CDCla, 500 MHz) 87,43 (1H, t, J = 7,5 Hz y 15,0 Hz, aromático), 7,33 (4H, m, aromático), 7,09 (3H, m, aromático), 4,71 (2H, s, CH2), 3,53 (2H, s, CH2), 3,23 (2H, s, CH2), 2,10 (2H, m, CH2), 1,59 (2H, m, CH2), 1,24 (2H, m, CH2), 1,10 (6 H, m, (CH sB 0,83 (3H, t, J = 7,5 Hz y 15,0 Hz, CH3). 1H NMR (CDCla, 500 MHz) 87.43 (1H, t, J = 7.5 Hz and 15.0 Hz, aromatic), 7.33 (4H, m, aromatic), 7.09 (3H, m , aromatic), 4.71 (2H, s, CH2), 3.53 (2H, s, CH2), 3.23 (2H, s, CH2), 2.10 (2H, m, CH2), 1, 59 (2H, m, CH2), 1.24 (2H, m, CH2), 1.10 (6H, m, (CH sB 0.83 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).

Ejemplo 34. Preparación de W,A/-d¡et¡l-4-(3-(W-(4-fluorofenil)pentanoam¡do)prop-1-¡n-1-¡l)benzam¡da (LMT-927) Se obtuvo W,W-d¡etil-4-(3-(A/-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n-1-¡l)benzam¡da (291,7 mg, rend¡m¡ento del 70 %) med¡ante el m¡smo método descr¡to en la Etapa 4 del Ejemplo 33 usando A/-(4-fluorofenil)pentanoamida (200 mg, 1,02 mmol) y metanosulfonato de 3-(4-W,A/-(diet¡lcarbamo¡l)fen¡l)prop-2-¡n-1-ilo.Example 34. Preparation of W, A / -d¡et¡l-4- (3- (W- (4-fluorophenyl) pentanoamide) prop-1-¡n-1-¡l) benzamide (LMT -927) Was obtained W, Wd¡ethyl-4- (3- (A / - (4-fluorophenyl) pentanoamide) prop-1-¡n-1-¡l) benzamida (291.7 mg, 70% yield) by the same method described in Step 4 of Example 33 using A / - (4-fluorophenyl) pentanoamide (200 mg, 1.02 mmol) and methanesulfonate 3- (4-W, A / - (diethylcarbamoyl) phenyl) prop-2-in-1-yl.

RMN de 1H (CDCla, 500 MHz) 87,31 (2H, d, J = 3,5 Hz, aromát¡co), 7,29 (4H, d, J = 3,0 Hz, aromát¡co), 7,15 (2H, t, J = 8,5 Hz y 17,0 Hz, aromát¡co), 4,71 (2H, s, CH2), 3,53 (2H, s, CH2), 3,23 (2H, s, CH2), 2,06 (2H, t, J = 7,5 Hz y 15.0 Hz, CH2), 1,57 (2H, m, CH2), 1,22 (2H, m, CH2), 1,10 (6H, s, (CHsk), 0,82 (3H, t, J = 7,5 Hz y 15,0 Hz, CH3). Ejemplo 35. Preparac¡ón de W-(3-(4-(A/,W-d¡et¡lsulfamo¡l)fenil)prop-2-¡n¡l)-A/-fen¡lpentanoam¡da (LMT-946) Etapa 1: Preparac¡ón de 4-bromo-A/.N-diet¡lbencenosulfonam¡da1H NMR (CDCla, 500 MHz) 87.31 (2H, d, J = 3.5 Hz, aromatic), 7.29 (4H, d, J = 3.0 Hz, aromatic), 7 , 15 (2H, t, J = 8.5 Hz and 17.0 Hz, aromatic), 4.71 (2H, s, CH2), 3.53 (2H, s, CH2), 3.23 ( 2H, s, CH2), 2.06 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.57 (2H, m, CH2), 1.22 (2H, m, CH2), 1.10 (6H, s, (CHsk), 0.82 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3). Example 35. Preparation of W- (3- (4- (A /, Wd¡et¡lsulfamo¡l) phenyl) prop-2-¡n¡l) -A / -phenylpentaneamide (LMT-946) Step 1: Preparation of 4-bromo-A / .N-dietlbenzenesulfonamide

Se d¡solv¡ó cloruro de 4-bromobencenosulfon¡lo (1,00 g, 3,91 mmol) en d¡clorometano (30,00 ml) y la mezcla se enfr¡ó en hielo. Se añad¡ó d¡et¡lam¡na (1,19 ml, 11,54 mmol) a la mezcla y la mezcla se agitó durante 5 m¡nutos, el h¡elo se ret¡ró y, después, la mezcla se agitó a temperatura amb¡ente durante 12 horas. La soluc¡ón de reacc¡ón se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con d¡clorometano y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSÜ4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex:EA=3:1), obten¡endo de este modo 4-bromo-W,W-dietilbencenosulfonam¡da (1,10 g, rend¡m¡ento del 96 %).4-Bromobenzenesulfonyl chloride (1.00 g, 3.91 mmol) was dissolved in dichloromethane (30.00 ml) and the mixture was cooled on ice. Dietlamine (1.19 ml, 11.54 mmol) was added to the mixture and the mixture was stirred for 5 minutes, the ice was removed, and then the mixture stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure and the residue obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 3: 1), thereby obtaining 4-bromo-W, W-diethylbenzenesulfonamide (1, 10 g, 96% yield).

RMN de 1H (CDCla, 500 MHz) 87,67 (4H, m), 3,23 (4H, c, J = 7,0 Hz), 1,13 (6H, t).1H NMR (CDCla, 500 MHz) 87.67 (4H, m), 3.23 (4H, q, J = 7.0 Hz), 1.13 (6H, t).

Etapa 2: Preparac¡ón de A/.N-d¡et¡l-4-(3-h¡drox¡prop-1-¡n¡l)bencenosulfonam¡daStep 2: Preparation of A / .N-d¡et¡l-4- (3-hydrox¡prop-1-¡n¡l) benzenesulfonamida

La 4-bromo-W,A/-diet¡lbencenosulfonam¡da (500,00 mg, 1,71 mmol) obten¡da en la Etapa 1 y alcohol propargíl¡co (0,20 ml, 3,42 mmol) se d¡solv¡eron en tr¡et¡lam¡na (10,00 ml) y la mezcla se agitó durante 5 m¡nutos. Se añad¡eron d¡cloruro de b¡s(tr¡fen¡lfosf¡na)palad¡o (II) (119,32 mg, 0,17 mmol) y yoduro de cobre (I) (32,37 mg, 0,17 mmol) a la mezcla, la mezcla se calentó a 60 °C, se somet¡ó a reflujo y se agitó durante 17 horas. La soluc¡ón de reacc¡ón se enfr¡ó a temperatura amb¡ente y se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSÜ4), se filtró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de sílice (Hex: EA=1: 1), obteniendo de este modo A/,W-dietil-4-(3-h¡drox¡prop-1-¡nil)bencenosulfonamida (286,00 mg, rendimiento del 63 %).The 4-bromo-W, A / -diethylbenzenesulfonamide (500.00 mg, 1.71 mmol) obtained in Step 1 and propargyl alcohol (0.20 ml, 3.42 mmol) were They were dissolved in tritlamine (10.00 ml) and the mixture was stirred for 5 minutes. Bis (triphephosphine) palladium (II) dichloride (119.32 mg, 0.17 mmol) and copper (I) iodide (32.37 mg, 0.17 mmol) to the mixture, the mixture was heated to 60 ° C, refluxed and stirred for 17 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate and washed with water. and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 1: 1), thereby obtaining A /, W-diethyl-4- (3-hydroxyprop- 1-Inyl) benzenesulfonamide (286.00 mg, 63% yield).

RMN de 1H (CDCh, 500 MHz) 8 7,66 (2H, d, J = 8,0 Hz), 7,42 (2H, d, J = 8,0 Hz), 4,44 (2H, s), 3,16 (4H, c, J = 7.0 Hz), 1,05 (6H, t).1H NMR (CDCh, 500 MHz) 8 7.66 (2H, d, J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz), 4.44 (2H, s) , 3.16 (4H, c, J = 7.0Hz), 1.05 (6H, t).

Etapa 3: Preparación de metanosulfonato de 3-(4-(N.A/-d¡et¡lsulfamoil)fen¡l)prop-2-¡n¡loStep 3: Preparation of 3- (4- (N.A / -d¡et¡lsulfamoyl) phen¡l) prop-2-¡n¡lo methanesulfonate

La A/,W-diet¡l-4-(3-h¡drox¡prop-1-¡n¡l)bencenosulfonam¡da (273,00 mg, 1,02 mmol) obtenida en la Etapa 2 se disolvió en diclorometano (10 ml) y la mezcla se enfrió en hielo. Se añadió trietilamina (0,21 ml, 1,53 mmol) a la mezcla y la mezcla se agitó durante 5 minutos. Se añadió cloruro de metanosulfonilo (0,09 ml, 1,12 mmol) a la misma temperatura, el hielo se retiró y la mezcla se agitó a temperatura ambiente durante 30 minutos. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSÜ4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex: EA=2:1), obteniendo de este modo metanosulfonato de 3-(4-(A/,W-diet¡lsulfamoil)fen¡l)prop-2-inilo (285,00 mg, rendimiento del 80 %).The A /, W-diethyl-4- (3-hydroxyprop-1-inl) benzenesulfonamide (273.00 mg, 1.02 mmol) obtained in Step 2 was dissolved in dichloromethane (10 ml) and the mixture was cooled on ice. Triethylamine (0.21 ml, 1.53 mmol) was added to the mixture and the mixture was stirred for 5 minutes. Methanesulfonyl chloride (0.09 ml, 1.12 mmol) was added at the same temperature, the ice was removed and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (Hex: EA = 2: 1), thereby obtaining 3- (4- (A /, W-diethylsulfamoyl) phenyl) prop-2 methanesulfonate -inyl (285.00 mg, 80% yield).

RMN de 1H (CDCh, 500 MHz) 8 7,73 (2H, d, J = 8,5 Hz), 7,53 (2H, d, J = 8,5 Hz), 5,05 (2H, s), 3,19 (4H, c, J = 7.0 Hz), 3,12 (3H, s), 1,07 (6H, t).1H NMR (CDCh, 500 MHz) 8 7.73 (2H, d, J = 8.5 Hz), 7.53 (2H, d, J = 8.5 Hz), 5.05 (2H, s) , 3.19 (4H, c, J = 7.0Hz), 3.12 (3H, s), 1.07 (6H, t).

Etapa 4: Preparación de 4-(3-bromoprop-1-¡n¡l)-A/.N-d¡etilbencenosulfonam¡daStep 4: Preparation of 4- (3-bromoprop-1-¡n¡l) -A / .N-d¡ethylbenzenesulfonam¡da

El metanosulfonato de 3-(4-(A/,W-diet¡lsulfamo¡l)fen¡l)prop-2-¡n¡lo (260,00 mg, 0,75 mmol) obtenido en la Etapa 3 se disolvió en tetrahidrofurano (20,00 ml) y la mezcla se enfrió en hielo. Se añadió bromuro de litio (196,28 mg, 2,26 mmol) a la mezcla a la m¡sma temperatura y la mezcla se ag¡tó durante 4 horas. La soluc¡ón de reacc¡ón se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSÜ4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó usando un filtro, obteniendo de este modo 4-(3-bromoprop-1-in¡l)-A/,W-d¡et¡lbencenosulfonam¡da (240,00 mg, 97 %).The 3- (4- (A /, W-diethylsulfamyl) phenyl) prop-2-ino (260.00 mg, 0.75 mmol) methanesulfonate obtained in Step 3 was dissolved in tetrahydrofuran (20.00 ml) and the mixture was cooled on ice. Lithium bromide (196.28 mg, 2.26 mmol) was added to the mixture at the same temperature and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified using a filter, thereby obtaining 4- (3-bromoprop-1-yl) -A /, W-di-ethylbenzenesulfonamide (240.00 mg, 97%).

Etapa 5: Preparación de A/.N-d¡et¡l-4-(3-(fen¡lam¡no)prop-1-¡nil)bencenosulfonam¡daStep 5: Preparation of A / .N-di-ethyl-4- (3- (phenylamine) prop-1-inyl) benzenesulfonamide

La 4-(3-bromoprop-1-in¡l)-W,A/-d¡et¡lbencenosulfonam¡da (248,00 mg, 0,75 mmol) obtenida en la Etapa 4 y carbonato de potasio (93,98 mg, 0,68 mmol) se disolvieron en acetonitrilo (15,00 ml) y la mezcla se agitó durante 30 minutos. The 4- (3-bromoprop-1-yl) -W, A / -d¡et¡lbenzenesulfonamida (248.00 mg, 0.75 mmol) obtained in Step 4 and potassium carbonate (93, 98 mg, 0.68 mmol) was dissolved in acetonitrile (15.00 ml) and the mixture was stirred for 30 minutes.

Se añadió anilina (0,06 ml, 0,68 mmol) a la mezcla y la mezcla se agitó a temperatura ambiente durante 9 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=2:1), obteniendo de este modo N,N-dietil-4-(3-(fenilamino)prop-1-inil)bencenosulfonamida (190,00 mg, rendimiento del 81 %).Aniline (0.06 ml, 0.68 mmol) was added to the mixture and the mixture was stirred at room temperature for 9 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 2: 1), thereby obtaining N, N-diethyl-4- (3- (phenylamino) prop-1-ynyl) benzenesulfonamide (190, 00 mg, 81% yield).

RMN de 1H (CDCla, 500 MHz) 87,71 (2H, d, J = 8,5 Hz), 7,46 (2H, d, J = 8,5 Hz), 7,23 (2H, t), 6,80 (1H, t), 6,73 (2H, d, J = 7,5 Hz), 4,15 (2H, s), 3,21 (4H, m), 1,10 (6H, t).1H NMR (CDCla, 500 MHz) 87.71 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.23 (2H, t), 6.80 (1H, t), 6.73 (2H, d, J = 7.5Hz), 4.15 (2H, s), 3.21 (4H, m), 1.10 (6H, t ).

Etapa 6: Preparación de N-(3-(4-(N.N-dietilsulfamoil)fenil)prop-2-inil)-N-fenilpentenamidaStep 6: Preparation of N- (3- (4- (N.N-diethylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentenamide

La N,N-dietil-4-(3-(fenilamino)prop-1-inil)bencenosulfonamida (174,00 mg, 0,51 mmol) obtenida en la Etapa 5 se disolvió en diclorometano (15,00 ml) y la mezcla se enfrió en hielo. Se añadió trietilamina (0,14 ml, 1,02 mmol) a la mezcla y la mezcla se agitó durante 5 minutos. Se añadió cloruro de valeroílo (0,06 ml, 0,53 mmol) a la misma temperatura, el hielo se retiró y la mezcla se agitó a temperatura ambiente durante 4 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex: EA=2:1), obteniendo de este modo N-(3-(4-(N,N-dietilsulfamoil)fenil)prop-2-inil)-N-fenilpentanoamida (153,00 mg, rendimiento del 70 %).The N, N-diethyl-4- (3- (phenylamino) prop-1-ynyl) benzenesulfonamide (174.00 mg, 0.51 mmol) obtained in Step 5 was dissolved in dichloromethane (15.00 ml) and the mixture was cooled on ice. Triethylamine (0.14 ml, 1.02 mmol) was added to the mixture and the mixture was stirred for 5 minutes. Valeroyl chloride (0.06 ml, 0.53 mmol) was added at the same temperature, the ice was removed and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 2: 1), thereby obtaining N- (3- (4- (N, N-diethylsulfamoyl) phenyl) prop-2-ynyl) - N-phenylpentanoamide (153.00 mg, 70% yield).

RMN de 1H (CDCla, 500 MHz) 87,74 (2H, d, J = 8,0 Hz), 7,51 (4H, m), 7,43 (3H, m), 4,73 (2H, s), 3,21 (4H, s), 2,11 (2H, t), 1,52 (2H, m), 1,21 (2H, m), 0,10 (6H, t), 0,80 (3H, t).1H NMR (CDCla, 500 MHz) 87.74 (2H, d, J = 8.0 Hz), 7.51 (4H, m), 7.43 (3H, m), 4.73 (2H, s ), 3.21 (4H, s), 2.11 (2H, t), 1.52 (2H, m), 1.21 (2H, m), 0.10 (6H, t), 0.80 (3H, t).

Ejemplo 36. Preparación de N-(3-(4-(N-isopropilsulfamoil)fenil)prop-2-inil)-N-fenilpentanoamida (LMT-947) Etapa 1: Preparación de 4-bromo-N-isopropilbencenosulfonamidaExample 36. Preparation of N- (3- (4- (N-isopropylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide (LMT-947) Step 1: Preparation of 4-bromo-N-isopropylbenzenesulfonamide

Se disolvió cloruro de 4-bromobencenosulfonilo (1,00 g, 3,91 mmol) en diclorometano (10,00 ml) y se añadieron isopropilamina (0,40 ml, 4,69 mmol) y piridina (0,41 ml, 5,09 mmol) a la mezcla y se agitaron a temperatura ambiente durante 2 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex: EA=3:1), obteniendo de este modo 4-bromo-A/-isopropilbencenosulfonamida (730,00 mg, rendimiento del 67 %).4-Bromobenzenesulfonyl chloride (1.00 g, 3.91 mmol) was dissolved in dichloromethane (10.00 ml) and isopropylamine (0.40 ml, 4.69 mmol) and pyridine (0.41 ml, 5 0.09 mmol) to the mixture and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 3: 1), thereby obtaining 4-bromo-A / -isopropylbenzenesulfonamide (730.00 mg, 67% yield).

RMN de 1H (CDCh, 500 MHz) 87,76-7,64 (4H, m), 3,47 (1H, m), 1,09 (6H, d, J = 7,0 Hz).1H NMR (CDCh, 500 MHz) 87.76-7.64 (4H, m), 3.47 (1H, m), 1.09 (6H, d, J = 7.0 Hz).

Etapa 2: Preparación de 4-(3-hidroxiprop-1-inil)-N-isopropilbencenosulfonamidaStep 2: Preparation of 4- (3-hydroxypropyl-1-ynyl) -N-isopropylbenzenesulfonamide

Se obtuvo 4-(3-hidroxiprop-1-inil)-N-isopropilbencenosulfonamida (420,00 mg, rendimiento del 92 %) mediante el mismo método descrito en la Etapa 2 del Ejemplo 35 usando la 4-bromo-N-isopropilbencenosulfonamida (500,00 mg, 1,80 mmol) obtenida en la Etapa 1 y alcohol propargílico (0,21 ml, 3,59 mmol).4- (3-Hydroxypropyl-1-ynyl) -N-isopropylbenzenesulfonamide (420.00 mg, 92% yield) was obtained by the same method described in Step 2 of Example 35 using the 4-bromo-N-isopropylbenzenesulfonamide ( 500.00 mg, 1.80 mmol) obtained in Step 1 and propargyl alcohol (0.21 ml, 3.59 mmol).

RMN de 1H (CDCh, 500 MHz) 87,81 (2H, d, J = 8,0 Hz), 7,49 (2H, d, J = 8,5 Hz), 4,51 (2H, s), 3,44 (1H, m), 1,06 (6H, d, J = 6,5 Hz).1H NMR (CDCh, 500 MHz) 87.81 (2H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.5 Hz), 4.51 (2H, s), 3.44 (1H, m), 1.06 (6H, d, J = 6.5 Hz).

Etapa 3: Preparación de metanosulfonato de 3-(4-(N-isopropilsulfamoil)fenil)prop-2-iniloStep 3: Preparation of 3- (4- (N-isopropylsulfamoyl) phenyl) prop-2-ynyl methanesulfonate

Se obtuvo metanosulfonato de 3-(4-(N-isopropilsulfamoil)fenil)prop-2-inilo (330,00 mg, rendimiento del 61 %) mediante el mismo método descrito en la Etapa 3 del Ejemplo 35 usando la 4-(3-hidroxiprop-1-inil)-N-isopropilbencenosulfonamida (410,00 mg, 1,62 mmol) obtenida en la Etapa 2 y cloruro de metanosulfonilo (0,14 ml, 1,78 mmol).3- (4- (N-isopropylsulfamoyl) phenyl) prop-2-ynyl methanesulfonate (330.00 mg, 61% yield) was obtained by the same method described in Step 3 of Example 35 using the 4- (3 -hydroxyprop-1-ynyl) -N-isopropylbenzenesulfonamide (410.00 mg, 1.62 mmol) obtained in Step 2 and methanesulfonyl chloride (0.14 ml, 1.78 mmol).

RMN de 1H (CDCh, 500 MHz) 87,86 (2H, d, J = 8,5 Hz), 7,59 (2H, d, J = 8,5 Hz), 5,10 (2H, s), 3,47 (1H, m) 3,17 (3H, s), 1,08 (6H, d, J = 6,5 Hz).1H NMR (CDCh, 500 MHz) 87.86 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.5 Hz), 5.10 (2H, s), 3.47 (1H, m) 3.17 (3H, s), 1.08 (6H, d, J = 6.5 Hz).

Etapa 4: Preparación de 4-(3-bromoprop-1-¡n¡l)-A/-¡soprop¡lbencenosulfonam¡daStep 4: Preparation of 4- (3-bromoprop-1-¡n¡l) -A / -¡soprop¡lbenzenesulfonam¡da

Se obtuvo 4-(3-bromoprop-1-inil)-N-isopropilbencenosulfonamida (190,00 mg, rendimiento del 95 %) mediante el mismo método descrito en la Etapa 4 del Ejemplo 35 usando el metanosulfonato de 3-(4-(N-isopropilsulfamoil)fenil)prop-2-inilo (210,00 mg, 0,63 mmol) obtenido en la Etapa 3 y bromuro de litio (165,00 mg, 1,90 mmol).4- (3-Bromoprop-1-ynyl) -N-isopropylbenzenesulfonamide (190.00 mg, 95% yield) was obtained by the same method described in Step 4 of Example 35 using the methanesulfonate of 3- (4- ( N-isopropylsulfamoyl) phenyl) prop-2-ynyl (210.00 mg, 0.63 mmol) obtained in Step 3 and lithium bromide (165.00 mg, 1.90 mmol).

Etapa 5: Preparación de N-¡soprop¡l-4-(3-(fen¡lam¡no)prop-1-¡n¡l)bencenosulfonam¡daStep 5: Preparation of N-isopropyl-4- (3- (phenylamine) prop-1-inil) benzenesulfonamide

Se obtuvo N-isopropil-4-(3-(fenilamino)prop-1-inil)bencenosulfonamida (157 mg, rendimiento del 83 %) usando la 4-(3-bromoprop-1-inil)-N-isopropilbencenosulfonamida (199,00 mg, 0,63 mmol) obtenida en la Etapa 4 y anilina (0,05 ml, 0,57 mmol).N-isopropyl-4- (3- (phenylamino) prop-1-ynyl) benzenesulfonamide (157 mg, 83% yield) was obtained using 4- (3-bromoprop-1-ynyl) -N-isopropylbenzenesulfonamide (199, 00 mg, 0.63 mmol) obtained in Step 4 and aniline (0.05 ml, 0.57 mmol).

RMN de 1H (CDCh, 500 MHz) 8 7,80 (2H, d, J = 9,0 Hz), 7,50 (2H, d, J = 8,5 Hz), 7,25 (2H, m), 6,82 (1H, t), 6,76 (2H, d, J = 8,0 Hz), 4,64 (1H, d, J = 8,0 Hz), 4,19 (2H, s), 3,45 (1H, m), 1,06 (6 H, d, J = 6,0 Hz).1H NMR (CDCh, 500 MHz) 8 7.80 (2H, d, J = 9.0 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.25 (2H, m) , 6.82 (1H, t), 6.76 (2H, d, J = 8.0 Hz), 4.64 (1H, d, J = 8.0 Hz), 4.19 (2H, s), 3.45 (1H, m), 1.06 (6H, d, J = 6.0Hz).

Etapa 6 : Preparación de N-(3-(4-(N-¡soprop¡lsulfamo¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡daStep 6: Preparation of N- (3- (4- (N-isopropylsulfamoil) phenyl) prop-2-innl) -N-phenylpentaneamide

Se obtuvo N-(3-(4-(N-¡soprop¡lsulfamo¡l)fen¡l)prop-2-¡n¡l)-N-fen¡lpentanoam¡da (94,00 mg, rend¡m¡ento del 49,5 %) med¡ante el m¡smo método descr¡to en la Etapa 6 del Ejemplo 35 usando la N-¡soprop¡l-4-(3-(fen¡lam¡no)prop-1-¡n¡l)bencenosulfonam¡da (150,00 mg, 0,46 mmol) obten¡da en la Etapa 2 y cloruro de valeroílo (0,06 ml, 0,48 mmol). RMN de 1H (CDCh, 500 MHz) 87,78 (2H, d, J = 8,5 Hz), 7,51-7,37 (7H, m), 4,72 (2H, s), 3,33 (1H, m), 2,10 (2H, t), 1,51 (2H, m), 1,19 (2H, m), 0,99 (6 H, d, J = 6,5 Hz), 0,78 (3H, t)N- (3- (4- (N-isopropylsulfamyl) phenyl) prop-2-nil) -N-phenylpentaneamide (94.00 mg, yield 49.5%) by the same method described in Step 6 of Example 35 using N-isopropyl-4- (3- (phenylamine) prop-1 -¡N¡l) benzenesulfonamida (150.00 mg, 0.46 mmol) obtained in Step 2 and valeroyl chloride (0.06 ml, 0.48 mmol). 1H NMR (CDCh, 500 MHz) 87.78 (2H, d, J = 8.5 Hz), 7.51-7.37 (7H, m), 4.72 (2H, s), 3.33 (1H, m), 2.10 (2H, t), 1.51 (2H, m), 1.19 (2H, m), 0.99 (6H, d, J = 6.5 Hz), 0.78 (3H, t)

Ejemplo 37. Preparac¡ón de 4-(3-(A/-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzoato de ferc-but¡lo (LMT-1012) Etapa 1: Preparac¡ón de A/-fen¡lpentanoam¡daExample 37. Preparation of 4- (3- (A / -phenylpentaneamide) prop-1-¡n-1-¡l) tert-butyl benzoate (LMT-1012) Step 1: Preparation ¡Ón of A / -fen¡lpentanoam¡da

Se d¡solv¡ó an¡l¡na (10,00 ml, 107,40 mmol) en d¡clorometano (150 ml) y la mezcla se enfr¡ó en h¡elo. Se añad¡ó tr¡et¡lam¡na (30,00 ml, 214,80 mmol) a la mezcla y la mezcla se ag¡tó durante 5 m¡nutos. Se añad¡ó cloruro de valeroílo (16,00 ml, 128,90 mmol) a la m¡sma temperatura, el h¡elo se ret¡ró y la mezcla se ag¡tó a temperatura amb¡ente durante 2 horas. La soluc¡ón de reacc¡ón se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex:EA=10:1), obten¡endo de este modo N-fen¡lpentanoam¡da (19,1 g, rend¡m¡ento del 99,9 %).Anil (10.00 ml, 107.40 mmol) was dissolved in dichloromethane (150 ml) and the mixture was cooled in ice. Triethylamine (30.00 ml, 214.80 mmol) was added to the mixture and the mixture was stirred for 5 minutes. Valeroyl chloride (16.00 ml, 128.90 mmol) was added at the same temperature, the ice was removed and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 10: 1), thus obtaining N- phenylpentaneamide (19.1 g, yield 99.9%).

RMN de 1H (CDCla, 500 MHz) 8 7,55 (2H, d, J = 8,0 Hz, aromát¡co), 7,29 (2H, t, J = 7,5 Hz y 15,0 Hz, aromát¡co), 7,09 (1H, t, J = 7,0 Hz y 14,5 Hz, aromát¡co), 2,35 (2H, t, J = 8,0 Hz y 15,5 Hz, CH2), 1,70 (2H, m, CH2), 1,37 (2H, m, CH2), 0,92 (3H, t, J = 7,0 Hz y 14,5 Hz, CH3).1H NMR (CDCla, 500 MHz) 8 7.55 (2H, d, J = 8.0 Hz, aromatic), 7.29 (2H, t, J = 7.5 Hz and 15.0 Hz, aromatic), 7.09 (1H, t, J = 7.0 Hz and 14.5 Hz, aromatic), 2.35 (2H, t, J = 8.0 Hz and 15.5 Hz, CH2), 1.70 (2H, m, CH2), 1.37 (2H, m, CH2), 0.92 (3H, t, J = 7.0 Hz and 14.5 Hz, CH3).

Etapa 2: Preparac¡ón de N-fen¡l-N-(prop-2-¡n-1-¡l)pentanoam¡daStep 2: Preparation of N-phenil-N- (prop-2-¡n-1-¡l) pentanoamide

La N-fen¡lpentanoam¡da (19,10 g, 107,40 mmol) obten¡da en la Etapa 1 se d¡solv¡ó en N,N-d¡met¡lformam¡da (DMF; 100 ml) y un s¡stema de reacc¡ón se sust¡tuyó con n¡trógeno, se añad¡ó h¡druro de sod¡o (5,20 g, 214,80 mmol) a una temperatura ¡nfer¡or a cero y, después, la mezcla se ag¡tó durante 2 horas. Se añad¡ó bromuro de proparg¡lo (18,10 ml, 214,80 mmol) a la mezcla y la mezcla se ag¡tó a una temperatura ¡nfer¡or a cero durante 2 horas. Se añad¡ó agua a la soluc¡ón de reacc¡ón a una temperatura ¡nfer¡or a cero, que después se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex:EA=9:1), obten¡endo de este modo N-fen¡l-N-(prop-2-¡n-1-¡l)pentanam¡da (19,20 g, rend¡m¡ento del 83 %).The N-phenylpentanoamide (19.10 g, 107.40 mmol) obtained in Step 1 was dissolved in N, Nd, methylformamide (DMF; 100 ml) and a The reaction system was replaced with nitrogen, sodium hydroxide (5.20 g, 214.80 mmol) was added at a temperature below zero, and then , the mixture was stirred for 2 hours. Propargyl bromide (18.10 ml, 214.80 mmol) was added to the mixture and the mixture was stirred at a temperature below zero for 2 hours. Water was added to the reaction solution at a temperature below zero, which was then diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 9: 1), thus obtaining N-phenylN- (prop-2-in- 1-11) pentanamide (19.20 g, 83% yield).

RMN de 1H (CDCla, 500 MHz) 8 7,42 (2H, m, aromát¡co), 7,37 (1H, d, J = 7,0 Hz, aromát¡co), 7,26 (2H, m, aromát¡co), 4,47 (2H, d, J = 2,0 Hz, CH2), 2,03 (2H, t, J = 7,0 Hz y 15,5 Hz, CH2), 1,53 (2H, m, CH2), 1,20 (2H, m, CH2), 0,77 (3H, t, J = 7,5 Hz y 15 Hz, CH3).1H NMR (CDCla, 500 MHz) 8 7.42 (2H, m, aromatic), 7.37 (1H, d, J = 7.0 Hz, aromatic), 7.26 (2H, m , aromatic), 4.47 (2H, d, J = 2.0 Hz, CH2), 2.03 (2H, t, J = 7.0 Hz and 15.5 Hz, CH2), 1.53 (2H, m, CH2), 1.20 (2H, m, CH2), 0.77 (3H, t, J = 7.5 Hz and 15 Hz, CH3).

Etapa 3: Preparac¡ón de 4-yodobenzoato de terc-but¡loStep 3: Preparation of tert-butyl 4-iodobenzoate

Se añad¡eron cloruro de t¡on¡lo (2,30 ml, 32,30 mmol) y N,N-d¡met¡lformam¡da (DMF) (0,02 ml, 0,20 mmol) a ác¡do 4-yodobenzo¡co (1,00 g, 4,00 mmol) y, después, el s¡stema de reacc¡ón se sust¡tuyó con n¡trógeno, se calentó a 75 °C, se somet¡ó a reflujo y, después, se ag¡tó durante 1 hora. La soluc¡ón de reacc¡ón se concentró a pres¡ón reduc¡da, el res¡duo obten¡do se d¡solv¡ó en tetrah¡drofurano (5 ml) y, después, se añad¡ó una soluc¡ón 1 M de ferc-butóx¡do de potas¡o en THF (4,5 ml) lentamente a una temperatura ¡nfer¡or a cero y la mezcla se ag¡tó durante 30 m¡nutos. La soluc¡ón de reacc¡ón se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con acetato de et¡lo y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de síl¡ce (Hex:EA=9:1), obten¡endo de este modo 4-yodobenzoato de 2-(tr¡met¡ls¡l¡l)et¡lo (14,00 g, rend¡m¡ento del 99,9 %).Thlonyl chloride (2.30 ml, 32.30 mmol) and N, Nd¡methylformamide (DMF) (0.02 ml, 0.20 mmol) were added to acid 4-iodobenzoic (1.00 g, 4.00 mmol) and then the reaction system was replaced with nitrogen, heated to 75 ° C, refluxed and then stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue obtained was dissolved in tetrahydrofuran (5 ml), and then a solution was added. 1 M potassium ferc-butoxide in THF (4.5 ml) slowly at a temperature below zero and the mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue obtained was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 9: 1), thereby obtaining 2- (trimethyl-4-iodobenzoate). 1) ethyl (14.00 g, 99.9% yield).

RMN de 1H (CDCl3, 400 MHz) 87,77 (2H, d, J = 7,5 Hz, aromát¡co), 7,69 (2H, d, J = 8,0 Hz, aromát¡co), 1,59 (9H, s, (CH3)3).1H NMR (CDCl3, 400 MHz) 87.77 (2H, d, J = 7.5 Hz, aromatic), 7.69 (2H, d, J = 8.0 Hz, aromatic), 1 , 59 (9H, s, (CH3) 3).

Etapa 4: Preparac¡ón de 4-(3-(N-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzoato de terc-but¡loStep 4: Preparation of tert-butyl 4- (3- (N-phenylpentaneamido) prop-1-¡n-1-¡l) benzoate

La N-fen¡l-N-(pro-2-¡n-1-¡l)pentanoam¡da (2,30 g, 10,70 mmol) obten¡da en la Etapa 2 se añad¡ó a una soluc¡ón en la que el 4-yodobenzoato de ferc-but¡lo (4,90 g, 16,00 mmol) obten¡do en la Etapa 3 se d¡solv¡ó en tetrah¡drofurano (30 ml) y un s¡stema de reacc¡ón se sust¡tuyó con n¡trógeno, segu¡do de ag¡tac¡ón a temperatura amb¡ente durante 5 m¡nutos. Se añad¡eron tr¡et¡lam¡na (24 ml), d¡cloruro de b¡s(tr¡fen¡lfosf¡na)palad¡o (II) (75,00 mg, 0,10 mmol) y yoduro de cobre (I) (41,00 mg, 0,21 mmol) a la mezcla y la mezcla se ag¡tó a temperatura amb¡ente durante 16 horas. El producto resultante se concentró a pres¡ón reduc¡da y el res¡duo obten¡do se d¡luyó con d¡clorometano y se lavó con agua y salmuera. Se recog¡ó una capa de d¡solvente orgán¡co, se desh¡drató con sulfato de magnes¡o anh¡dro (MgSO4), se f¡ltró y, después, se concentró a pres¡ón reduc¡da. El concentrado se pur¡f¡có med¡ante cromatografía en columna sobre gel de sílice (Hex:EA=4:1), obteniendo de este modo 4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzoato de ferc-butilo (3,30 g, rendimiento del 78,3 %).The N-phenylN- (pro-2-¡n-1-¡l) pentanoamide (2.30 g, 10.70 mmol) obtained in Step 2 was added to a solution in which the tert-butyl 4-iodobenzoate (4.90 g, 16.00 mmol) obtained in Step 3 was dissolved in tetrahydrofuran (30 ml) and a system Reaction was replaced with nitrogen, followed by agitation at room temperature for 5 minutes. Triethylamine (24 ml), b¡s (triphenophosphine) palladium (II) chloride (75.00 mg, 0.10 mmol) and copper (I) iodide (41.00 mg, 0.21 mmol) to the mixture and the mixture was stirred at room temperature for 16 hours. The resulting product was concentrated under reduced pressure and the residue obtained was diluted with dichloromethane and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by chromatography in column on silica gel (Hex: EA = 4: 1), thus obtaining tert-butyl 4- (3- (A / -phenylpentanoamido) prop-1-in-1-yl) benzoate (3.30 g , 78.3% yield).

RMN de 1H (500 MHz, CDCla): 87,88 (2H, d, J = 8,0 Hz, aromático), 7,45 (2H, m, aromático), 7,39 (1H, d, J = 7,0 Hz, aromático), 7,35 (2H, d, J = 8,0 Hz, aromático), 7,30 (2H, d, J = 5,0 Hz, aromático), 4,72 (2H, s, CH2), 2,07 (2H, t, J = 7,5 Hz y 15 Hz, CH2), 1,56 (2H, m, CH2), 1,51 (9H, s, (CHa)a), 1,22 (2H, m, CH2), 0,80 (3H, t, 7,5 Hz y 15 Hz, 7,5 Hz y 15 Hz, CH3).1H NMR (500 MHz, CDCla): 87.88 (2H, d, J = 8.0 Hz, aromatic), 7.45 (2H, m, aromatic), 7.39 (1H, d, J = 7 , 0 Hz, aromatic), 7.35 (2H, d, J = 8.0 Hz, aromatic), 7.30 (2H, d, J = 5.0 Hz, aromatic), 4.72 (2H, s , CH2), 2.07 (2H, t, J = 7.5 Hz and 15 Hz, CH2), 1.56 (2H, m, CH2), 1.51 (9H, s, (CHa) a), 1.22 (2H, m, CH2), 0.80 (3H, t, 7.5 Hz and 15 Hz, 7.5 Hz and 15 Hz, CH3).

Ejemplo 38. Preparación de ácido 4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzoico (LMT-1013)Example 38. Preparation of 4- (3- (A / -phenylpentanoamido) prop-1-yn-1-yl) benzoic acid (LMT-1013)

El 4-(3-(W-fenilpentanoamido)prop-1-in-1-il)benzoato de ferc-butilo (2,00 g, 5,10 mmol) obtenido en el Ejemplo 37 se disolvió en acetonitrilo (48 ml) y la mezcla se agitó a una temperatura inferior a cero durante 5 minutos. Se añadió ácido trifluoroacético (12 ml) lentamente a la solución y la mezcla se agitó a temperatura ambiente durante 48 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (HEX:EA=2:1), obteniendo de este modo ácido 4-(3-(A/-fenilpentanoamido)pro-1-in-1-il)benzoico (1,6 g, rendimiento del 95 %).The tert-butyl 4- (3- (W-phenylpentanoamido) prop-1-yn-1-yl) benzoate (2.00 g, 5.10 mmol) obtained in Example 37 was dissolved in acetonitrile (48 ml) and the mixture was stirred at a temperature below zero for 5 minutes. Trifluoroacetic acid (12 ml) was added slowly to the solution and the mixture was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (HEX: EA = 2: 1), thereby obtaining 4- (3- (A / -phenylpentaneamido) pro-1-yn-1-yl) benzoic acid ( 1.6 g, 95% yield).

RMN de 1H (500 MHz, MeOD): 8 7,95 (2H, d, J = 8,5 Hz, aromático), 7,51 (2H, m, aromático), 7,45 (1H, m, aromático), 7,44 (2H, d, J = 8,5 Hz, aromático), 7,39 (2H, d, J = 8,0 Hz, aromático), 4,73 (2H, s, CH2), 2,11 (2H, t, CH3), 1,21 (2H, m, CH2), 0,83 (3H, t, CH3).1H NMR (500 MHz, MeOD): 8 7.95 (2H, d, J = 8.5 Hz, aromatic), 7.51 (2H, m, aromatic), 7.45 (1H, m, aromatic) , 7.44 (2H, d, J = 8.5 Hz, aromatic), 7.39 (2H, d, J = 8.0 Hz, aromatic), 4.73 (2H, s, CH2), 2, 11 (2H, t, CH3), 1.21 (2H, m, CH2), 0.83 (3H, t, CH3).

Ejemplo 39. Preparación de W-etil-4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzamida (LMT-1017)Example 39. Preparation of W-ethyl-4- (3- (A / -phenylpentaneamido) prop-1-in-1-yl) benzamide (LMT-1017)

El ácido 4-(3-(W-fenilpentanoamido)prop-1-in-1-il)benzoico (80,00 mg, 0,24 mmol) obtenido en el Ejemplo 38 se disolvió en W,W-dimetilformamida (DMF; 0,70 ml), clorhidrato de etilamina (29,20 mg, 0,36 mmol) e hidrato de 1-hidroxibenzotriazol (48,4 mg, 0,36 mmol), que se agitaron en trietilamina (0,70 ml) durante 1 hora, y se añadió clorhidrato de 1-etil-3-(3-dimetilaminopropil)carbodiimida (55,5 mg, 0,36 mmol) a la solución y, después, la mezcla se agitó a temperatura ambiente durante 16 horas. La solución de reacción se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=1:1), obteniendo de este modo W-etil-4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzamida (56,8 mg, rendimiento del 66 %).The 4- (3- (W-phenylpentanoamido) prop-1-in-1-yl) benzoic acid (80.00 mg, 0.24 mmol) obtained in Example 38 was dissolved in W, W-dimethylformamide (DMF; 0.70 ml), ethylamine hydrochloride (29.20 mg, 0.36 mmol) and 1-hydroxybenzotriazole hydrate (48.4 mg, 0.36 mmol), which were stirred in triethylamine (0.70 ml) for 1 hour, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (55.5 mg, 0.36 mmol) was added to the solution, and then the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 1: 1), thereby obtaining W-ethyl-4- (3- (A / -phenylpentanoamido) prop-1-in-1-yl ) benzamide (56.8 mg, 66% yield).

RMN de 1H (CDCla, 500 MHz) 87,69 (2H, d, J = 8,5 Hz, aromático), 7,39 (7H, m, aromático), 4,72 (2H, s, CH2), 3,49 (2H, t, J = 6,0 Hz y 13,0 Hz, CH2), 2,08 (2H, t, J = 7,5 Hz y 15,0 Hz, CH2), 1,57 (2H, m, CH2), 1,23 (2H, m, CH2), 0,81 (3H, t, J = 7,5 Hz y 14,5 Hz, CH3).1H NMR (CDCla, 500 MHz) 87.69 (2H, d, J = 8.5 Hz, aromatic), 7.39 (7H, m, aromatic), 4.72 (2H, s, CH2), 3 , 49 (2H, t, J = 6.0 Hz and 13.0 Hz, CH2), 2.08 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.57 (2H , m, CH2), 1.23 (2H, m, CH2), 0.81 (3H, t, J = 7.5 Hz and 14.5 Hz, CH3).

Ejemplo 40. Preparación de W-(2-(dimetilamino)etil)-4-(3-(W-fenilpentanoamido)prop-1-in-1-il)benzamida (LMT-1016) Example 40. Preparation of W- (2- (dimethylamino) ethyl) -4- (3- (W-phenylpentanoamido) prop-1-yn-1-yl) benzamide (LMT-1016)

Se obtuvo W-(2-(dietilamino)etil)-4-(3-(W-fenilpentanoamido)prop-1-in-1-il)benzamida (71,72 mg, rendimiento del 74 %) mediante el mismo método descrito en el Ejemplo 39 usando el ácido 4-(3-(A/-fenilpentanoamido)pro-1-in-1-il)benzoico (80,00 mg, 0,24 mmol) obtenido en el Ejemplo 38 y N,N-dimetiletano-1,2-diamina (0,04 ml, 0,36 mmol). RMN de 1H (CDCh, 500 MHz) 87,71 (2H, d, J = 8,0 Hz, aromático), 7,38 (7H, m, aromático), 4,70 (2H, s, CH2), 3,48 (2H, m, CH2), 2,50 (2H, t, J = 6,0 Hz y 11,5 Hz, CH2), 2,24 (6H, s, ( C ^ B 2,05 (2H, t, J = 7,5 Hz y 15,0 Hz, CH2), 1,54 (2H, m, CH2), 1,20 (2H, m, CH2), 0,78 (3H, t, J = 7,0 Hz y 14,0 Hz, CH3).W- (2- (diethylamino) ethyl) -4- (3- (W-phenylpentanoamido) prop-1-in-1-yl) benzamide (71.72 mg, 74% yield) was obtained by the same method described in Example 39 using the 4- (3- (A / -phenylpentanoamido) pro-1-in-1-yl) benzoic acid (80.00 mg, 0.24 mmol) obtained in Example 38 and N, N- dimethylethane-1,2-diamine (0.04 ml, 0.36 mmol). 1H NMR (CDCh, 500 MHz) 87.71 (2H, d, J = 8.0 Hz, aromatic), 7.38 (7H, m, aromatic), 4.70 (2H, s, CH2), 3 , 48 (2H, m, CH2), 2.50 (2H, t, J = 6.0 Hz and 11.5 Hz, CH2), 2.24 (6H, s, (C ^ B 2.05 (2H , t, J = 7.5 Hz and 15.0 Hz, CH2), 1.54 (2H, m, CH2), 1.20 (2H, m, CH2), 0.78 (3H, t, J = 7.0 Hz and 14.0 Hz, CH3).

Ejemplo 41. Preparación de 2-(4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzamido)acetato de etilo (LMT-1014) Example 41. Preparation of ethyl 2- (4- (3- (A / -phenylpentaneamido) prop-1-in-1-yl) benzamido) acetate (LMT-1014)

Se obtuvo 2-(4-(3-(W-fenilpentanoamido)prop-1-in-1-il)benzamido)acetato de etilo (102,18 mg, rendimiento del 54 %) mediante el mismo método descrito en el Ejemplo 39 usando el ácido 4-(3-(W-fenilpentanoamido)pro-1-in-1-il)benzoico (150,00 mg, 0,45 mmol) obtenido en el Ejemplo 38 y clorhidrato de éster etílico de glicina (93,70 mg, 0,67 mmol).Ethyl 2- (4- (3- (W-phenylpentanoamido) prop-1-in-1-yl) benzamido) acetate (102.18 mg, 54% yield) was obtained by the same method described in Example 39 using 4- (3- (W-phenylpentanoamido) pro-1-in-1-yl) benzoic acid (150.00 mg, 0.45 mmol) obtained in Example 38 and glycine ethyl ester hydrochloride (93, 70 mg, 0.67 mmol).

RMN de 1H (CDCh, 500 MHz) 87,74 (2H, d, J = 8,0 Hz, aromático), 7,37 (7H, m, aromático), 4,22 (4H, m, (CH2B 2,07 (2H, t, J = 7,5 Hz y 15,0 Hz, CH2), 1,56 (2H, m, CH2), 1,30 (5H, m, CH3, CH2), 1,22 (2H, m, CH2), 0,80 (3H, t, J = 7,5 Hz y 14,5 Hz, CH3).1H NMR (CDCh, 500 MHz) 87.74 (2H, d, J = 8.0 Hz, aromatic), 7.37 (7H, m, aromatic), 4.22 (4H, m, (CH2B 2, 07 (2H, t, J = 7.5 Hz and 15.0 Hz, CH2), 1.56 (2H, m, CH2), 1.30 (5H, m, CH3, CH2), 1.22 (2H , m, CH2), 0.80 (3H, t, J = 7.5 Hz and 14.5 Hz, CH3).

Ejemplo 42. Preparación de ácido 2-(4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzamido)acético (LMT-1015) Example 42. Preparation of 2- (4- (3- (A / -phenylpentanoamido) prop-1-in-1-yl) benzamido) acetic acid (LMT-1015)

El 2-(4-(3-(A/-fenilpentanoamido)prop-1-in-1-il)benzamido)acetato de etilo (46,20 mg, 0,10 mmol) obtenido en el Ejemplo 41 y una solución acuosa 2M de hidróxido de sodio (0,07 ml, 0,14 mmol) se disolvieron en metanol (0,1 ml) y la mezcla se agitó a temperatura ambiente durante 30 minutos. La acidez de la solución de reacción se aumentó usando ácido clorhídrico, que después se diluyó con etilacetato y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se recristalizó usando hexeno y etilacetato, obteniendo de este modo ácido 2-(4-(3-(W-fenilpentanoamido)prop-1-in-1-il)benzamido)acético (20,80 mg, rendimiento del 53 %).Ethyl 2- (4- (3- (A / -phenylpentanoamido) prop-1-in-1-yl) benzamido) acetate (46.20 mg, 0.10 mmol) obtained in Example 41 and an aqueous solution 2M sodium hydroxide (0.07 ml, 0.14 mmol) was dissolved in methanol (0.1 ml) and the mixture was stirred at room temperature for 30 minutes. The acidity of the reaction solution was increased using hydrochloric acid, which was then diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was recrystallized using hexene and ethyl acetate, thereby obtaining 2- (4- (3- (W-phenylpentanoamido) prop-1-in-1-yl) benzamido) acetic acid (20.80 mg, 53% yield ).

RMN de 1H (CDCh, 500 MHz) 87,71 (2H, d, J = 8,5 Hz, aromático), 7,40 (7H, m, aromático), 4,71 (2H, s, CH2), 4,23 (2H, d, J = 5,0 Hz, CH2), 2,10 (2H, t, J = 7,5 Hz y 15,5 Hz, CH2), 1,56 (2H, m, CH2), 1,22 (2H, m, CH2), 0,80 (3H, t, J = 7,0 Hz y 14,5 Hz, CH3).1H NMR (CDCh, 500 MHz) 87.71 (2H, d, J = 8.5 Hz, aromatic), 7.40 (7H, m, aromatic), 4.71 (2H, s, CH2), 4 , 23 (2H, d, J = 5.0 Hz, CH2), 2.10 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.56 (2H, m, CH2) , 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.0 Hz and 14.5 Hz, CH3).

Ejemplo 43. Preparación de 2-(4-(3-(A/-fenilpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)propanoato de metilo (LMT-1018)Example 43. Preparation of methyl 2- (4- (3- (A / -phenylpentanoamide) prop-1-¡n-1-¡l) benzamide) propanoate (LMT-1018)

Se obtuvo 2-(4-(3-(W-fenilpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)propanoato de metilo (110,00 mg, rendimiento delMethyl 2- (4- (3- (W-phenylpentanoamide) prop-1-¡n-1-¡l) benzamide) propanoate (110.00 mg, yield of

42 %) usando el ácido 4-(3-(W-fenilpentanoam¡do)pro-1-¡n-1-¡l)benzo¡co (100,00 mg, 0,30 mmol) obtenido en el Ejemplo 38 y clorhidrato de éster metílico de L-alanina (83,70 mg, 0,60 mmol).42%) using the 4- (3- (W-phenylpentanoamide) pro-1-¡n-1-¡l) benzoic acid (100.00 mg, 0.30 mmol) obtained in Example 38 and L-alanine methyl ester hydrochloride (83.70 mg, 0.60 mmol).

RMN de 1H (CDCla, 500 MHz) 87,72 (2H, d, J = 8,5 Hz, aromático), 7,37 (7H, m, aromático), 4,76 (1H, t, J 14.5 Hz CH), 4,71 (2H, s, CH2), 3,76 (3H, s, CH3), 2,06 (2H, t, J = 7,5 Hz y 15,5 Hz, CH2), 1,53 (2H, m, CH2), 1,501H NMR (CDCla, 500 MHz) 87.72 (2H, d, J = 8.5 Hz, aromatic), 7.37 (7H, m, aromatic), 4.76 (1H, t, J 14.5 Hz CH ), 4.71 (2H, s, CH2), 3.76 (3H, s, CH3), 2.06 (2H, t, J = 7.5 Hz and 15.5 Hz, CH2), 1.53 (2H, m, CH2), 1.50

(3H, d, J = 7,5 Hz, CH3), 1,20 (2H, m, CH2), 0,79 (3H, t, J = 7,5 Hz y 15,0 Hz, CH3).(3H, d, J = 7.5 Hz, CH3), 1.20 (2H, m, CH2), 0.79 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).

Ejemplo 44. Preparación de ácido 2-(4-(3-(A/-fenilpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)propano¡co (LMT-1019)Example 44. Preparation of 2- (4- (3- (A / -phenylpentane) prop-1-¡n-1-¡l) benzam¡do) propano¡co acid (LMT-1019)

Se obtuvo ácido 2-(4-(3-(A/-fen¡lpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)propanoico (45,00 mg, rendimiento del 55 %) usando el 2-(4-(3-(W-fenilpentanoam¡do)prop-1-¡n-1-¡l)benzam¡do)propanoato de metilo (86,50 mg, 0,20 mmol) obtenido en el Ejemplo 43.2- (4- (3- (A / -phenylpentane) prop-1-¡n-1-¡l) benzamide) propanoic acid (45.00 mg, 55% yield) was obtained using methyl 2- (4- (3- (W-phenylpentanoamide) prop-1-¡n-1-¡l) benzamide) propanoate (86.50 mg, 0.20 mmol) obtained in the Example 43.

RMN de 1H (CDCla, 500 MHz) 87,71 (2H, d, J = 8,0 Hz, aromático), 7,40 (7H, m, aromático), 4,76 (1H, t, J 14.5 Hz, CH), 4,72 (2H, s, CH2), 2,10 (2H, t, J = 7,5

Figure imgf000022_0001
15,5 Hz, CH2), 1,57 (5H, m, CH3, CH2), 1,22 (2H, m, CH2), 0,80 (3H, t, J = 7,5 Hz y 15,0 Hz, CH3).1H NMR (CDCla, 500 MHz) 87.71 (2H, d, J = 8.0 Hz, aromatic), 7.40 (7H, m, aromatic), 4.76 (1H, t, J 14.5 Hz, CH), 4.72 (2H, s, CH2), 2.10 (2H, t, J = 7.5
Figure imgf000022_0001
15.5 Hz, CH2), 1.57 (5H, m, CH3, CH2), 1.22 (2H, m, CH2), 0.80 (3H, t, J = 7.5 Hz and 15.0 Hz, CH3).

Ejemplo 45. Preparación de ácido 2-(4-(3-(A/-(3-fluorofenil)pentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡co (LMT-1009)Example 45. Preparation of 2- (4- (3- (A / - (3-fluorophenyl) pentanoamide) prop-1-nil) phenoxy) acetic acid (LMT-1009)

Etapa 1: Preparación de A/-(3-fluorofenil)pentanoam¡daStep 1: Preparation of A / - (3-fluorophenyl) pentanoamide

Se obtuvo A/-(3-fluorofenil)pentanoamida (349,00 mg, rendimiento del 99 %) mediante el mismo método descrito en la Etapa 1 del Ejemplo 37 usando 3-fluoroanilina (200,00 mg, 1,79 mmol).A / - (3-fluorophenyl) pentanoamide (349.00 mg, 99% yield) was obtained by the same method described in Step 1 of Example 37 using 3-fluoroaniline (200.00 mg, 1.79 mmol).

RMN de 1H (CDCh, 500 MHz) 88,10 (1H, s), 7,51 (1H, d, J = 11,0 Hz), 7,20 (2H, m), 6,79 (1H, m), 2,36 (2H, t), 1,681H NMR (CDCh, 500 MHz) 88.10 (1H, s), 7.51 (1H, d, J = 11.0 Hz), 7.20 (2H, m), 6.79 (1H, m ), 2.36 (2H, t), 1.68

(2H, m), 1,36 (2H, m), 0,91 (3H, t)(2H, m), 1.36 (2H, m), 0.91 (3H, t)

Etapa 2: Preparación de A/-(3-fluorofen¡l)-A/-(prop-2-¡nil)pentanoam¡daStep 2: Preparation of A / - (3-fluorophenil) -A / - (prop-2-inyl) pentanoamide

La W-(3-fluorofenil)pentanoamida (400,00 mg, 2,05 mmol) obtenida en la Etapa 1, hidróxido de potasio (230,61 mg,The W- (3-fluorophenyl) pentanoamide (400.00 mg, 2.05 mmol) obtained in Step 1, potassium hydroxide (230.61 mg,

4,11 mmol) y yoduro de tetrabutil amonio (37,87 mg, 0,20 mmol) se disolvieron en tetrahidrofurano (20,00 ml) y la mezcla se agitó durante 20 minutos. Se añadió bromuro de propargilo (0,19 ml, 2,30 mmol) a la mezcla a la misma temperatura y la mezcla se agitó durante 20 horas. La solución de reacción se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna sobre gel de sílice (Hex:EA=10:1), obteniendo de este modo A/-(3-fluorofenil)-A/-(prop-2-¡n¡l)pentanoam¡da (450,00 mg, rendimiento del 94 %).4.11 mmol) and tetrabutyl ammonium iodide (37.87 mg, 0.20 mmol) were dissolved in tetrahydrofuran (20.00 ml) and the mixture was stirred for 20 minutes. Propargyl bromide (0.19 ml, 2.30 mmol) was added to the mixture at the same temperature and the mixture was stirred for 20 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (Hex: EA = 10: 1), thereby obtaining A / - (3-fluorophenyl) -A / - (prop-2-¡n¡l) pentanoam¡ gives (450.00 mg, 94% yield).

RMN de 1H (CDCh, 500 MHz) 87,42 (1H, m), 7,11 (2H, m), 7,20 (1H, d, J = 9,0 Hz), 4,46 (2H, s), 2,07 (2H, t), 1,561H NMR (CDCh, 500 MHz) 87.42 (1H, m), 7.11 (2H, m), 7.20 (1H, d, J = 9.0 Hz), 4.46 (2H, s ), 2.07 (2H, t), 1.56

(2H, m), 1,22 (2H, m), 0,82 (3H, t)(2H, m), 1.22 (2H, m), 0.82 (3H, t)

Etapa 3: Preparación de A/-(3-fluorofen¡l)-A/-(3-(4-h¡drox¡fen¡l)prop-2-¡nil)pentanoam¡daStep 3: Preparation of A / - (3-fluorophenil) -A / - (3- (4-hydroxyphenyl) prop-2-inyl) pentanoamide

Se obtuvo W-(3-fluorofenil)-W-(3-(4-h¡drox¡fen¡l)prop-2-¡nil)pentanoam¡da (128,00 mg, rendimiento del 67,8 %) usando la W-(3-fluorofenil)-W-(prop-2-in¡l)pentanoam¡da (270,00 mg, 1,16 mmol) obtenida en la Etapa 2 y 4-yodofenol (127,60 mg, 0,58 mmol).W- (3-fluorophenyl) -W- (3- (4-hydroxyphenyl) prop-2-inyl) pentanoamide (128.00 mg, 67.8% yield) was obtained using the W- (3-fluorophenyl) -W- (prop-2-yl) pentanoamide (270.00 mg, 1.16 mmol) obtained in Step 2 and 4-iodophenol (127.60 mg, 0 , 58 mmol).

RMN de 1H (CDCh, 500 MHz) 87,51 (1H, m), 7,21 (5H, m), 6,71 (2H, d, J = 9,0 Hz), 7,65 (2H, s), 2,13 (2H, t), 1,541H NMR (CDCh, 500 MHz) 87.51 (1H, m), 7.21 (5H, m), 6.71 (2H, d, J = 9.0 Hz), 7.65 (2H, s ), 2.13 (2H, t), 1.54

(2H, m), 1,26 (2H, m), 0,82 (3H, t)(2H, m), 1.26 (2H, m), 0.82 (3H, t)

Etapa 4: Preparación de 2-(4-(3-(N-(3-fluorofen¡l)pentanoam¡do)prop-1-¡nilfenox¡)acetato de etiloStep 4: Preparation of ethyl 2- (4- (3- (N- (3-fluorophenyl) pentanoamide) prop-1-nylphenoxy) acetate

Se obtuvo 2-(4-(3-(A/-(3-fluorofenil)pentanoam¡do)prop-1-¡n¡l)fenox¡)acetato de etilo (113,00 mg, rendimiento delEthyl 2- (4- (3- (A / - (3-fluorophenyl) pentanoamide) prop-1-nil) phenoxy) acetate (113.00 mg, yield of

74 %) usando la A/-(3-fluorofen¡l)-A/-(3-(4-hidrox¡fen¡l)prop-2-¡n¡l)pentanoam¡da (120,00 mg, 0,37 mmol) obtenida en la Etapa 3 y carbonato de potasio (153,41 mg, 1,11 mmol).74%) using the A / - (3-fluorophenyl) -A / - (3- (4-hydroxyphenyl) prop-2-¡n¡l) pentanoamide (120.00 mg, 0 , 37 mmol) obtained in Step 3 and potassium carbonate (153.41 mg, 1.11 mmol).

RMN de 1H (CDCh, 500 MHz) 87,42 (1H, m), 7,28 (2H, d, J = 9,0 Hz), 7,09 (3H, m), 6,81 (2H, d, J = 9,0 Hz), 4,681H NMR (CDCh, 500 MHz) 87.42 (1H, m), 7.28 (2H, d, J = 9.0 Hz), 7.09 (3H, m), 6.81 (2H, d , J = 9.0 Hz), 4.68

(2H, s), 4,61 (2H, s), 4,27 (2H, m), 2,05 (2H, t), 1,58 (2H, m), 1,26 (5H, m), 0,82 (3H, t)(2H, s), 4.61 (2H, s), 4.27 (2H, m), 2.05 (2H, t), 1.58 (2H, m), 1.26 (5H, m) , 0.82 (3H, t)

Etapa 5: Preparación de ácido 2-(4-(3-(N-(3-fluorofen¡l)pentanoam¡do)prop-1-in¡l)fenox¡)acét¡coStep 5: Preparation of 2- (4- (3- (N- (3-fluorophenyl) pentanoamide) prop-1-yl) phenoxy) acetic acid

El 2-(4-(3-(W-(3-fluorofenil)pentanoamido)prop-1-¡n¡l)fenox¡)acetato de etilo (100,00 mg, 0,24 mmol) obtenido en la Etapa 4 se disolvió en etanol (9,00 ml) y la mezcla se agitó durante 5 minutos. Se añadió hidróxido de sodio 2 MEthyl 2- (4- (3- (W- (3-fluorophenyl) pentanoamido) prop-1-¡n¡l) phenox¡) acetate (100.00 mg, 0.24 mmol) obtained in Step 4 It was dissolved in ethanol (9.00 ml) and the mixture was stirred for 5 minutes. 2M sodium hydroxide was added

(0,30 ml) a la mezcla, la mezcla se calentó a 80 °C, se sometió a reflujo y se agitó durante 3 horas. La solución de reacción se enfrió a temperatura ambiente y se concentró a presión reducida y el residuo obtenido se diluyó con acetato de etilo y se lavó con agua y salmuera. Se recogió una capa de disolvente orgánico, se deshidrató con sulfato de magnesio anhidro (MgSO4), se filtró y, después, se concentró a presión reducida. El concentrado se purificó mediante cromatografía en columna ODS (MeOD:H2O=2 :1 ), obteniendo de este modo ácido 2-(4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético (15,00 mg, rendimiento del 16 %)(0.30 ml) to the mixture, the mixture was heated to 80 ° C, refluxed and stirred for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with water and brine. An organic solvent layer was collected, dehydrated with anhydrous magnesium sulfate (MgSO4), filtered, and then concentrated under reduced pressure. The concentrate is purified by column chromatography ODS (MeOD: H2O = 2: 1), thereby obtaining 2- (4- (3- (N- (3-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid (15 0.00 mg, 16% yield)

RMN de 1H (CDCI3, 500 MHz) 8 7,52 (1H, d, J = 7,0 Hz), 7,24 (5H, m), 6,88 (2H, d, J = 8,5 Hz), 4,68 (2H, s), 4,66 (2H, s), 2,14 (2H, t), 1,55 (2H, m), 1,24 (2H, m), 0,83 (3H, t)1H NMR (CDCI3, 500 MHz) 8 7.52 (1H, d, J = 7.0 Hz), 7.24 (5H, m), 6.88 (2H, d, J = 8.5 Hz) , 4.68 (2H, s), 4.66 (2H, s), 2.14 (2H, t), 1.55 (2H, m), 1.24 (2H, m), 0.83 ( 3H, t)

Ejemplo 46. Preparación de ácido 2-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético (LMT-1010) Etapa 1: Preparación de N-(4-fluorofenil)pentanoam¡daExample 46. Preparation of 2- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid (LMT-1010) Step 1: Preparation of N- (4-fluorophenyl) pentanoam¡da

Se obtuvo N-(4-fluorofenil)pentanoamida (870,00 mg, rendimiento del 99 %) mediante el mismo método descrito en la Etapa 1 del Ejemplo 37 usando 4-fluoroanilina (500,00 mg, 4,49 mmol) y cloruro de valeroílo (1,10 ml, 8,99 mmol). RMN de 1H (CDCh, 400 MHz) 88,16 (1H, a), 7,48-7,45 (2H, m), 6,97-6,94 (2H, m), 2,34-2,31 (2H, t), 1,68-1,65 (2H, m), 1,38-1,33 (2H, m), 0,92-0,89 (3H, t).N- (4-fluorophenyl) pentanoamide (870.00 mg, 99% yield) was obtained by the same method described in Step 1 of Example 37 using 4-fluoroaniline (500.00 mg, 4.49 mmol) and chloride of valeroyl (1.10 ml, 8.99 mmol). 1H NMR (CDCh, 400 MHz) 88.16 (1H, a), 7.48-7.45 (2H, m), 6.97-6.94 (2H, m), 2.34-2, 31 (2H, t), 1.68-1.65 (2H, m), 1.38-1.33 (2H, m), 0.92-0.89 (3H, t).

Etapa 2: Preparación de N-(4-fluorofenil)-N-(prop-2-inil)pentanoamidaStep 2: Preparation of N- (4-fluorophenyl) -N- (prop-2-ynyl) pentanoamide

Se obtuvo N-(4-fluorofenil)-N-(prop-2-inil)pentanoamida (347,60 mg, rendimiento del 57 %) mediante el mismo método descrito en la Etapa 2 del Ejemplo 45 usando la N-(4-fluorofenil)pentanoamida (500,00 mg, 2,56 mmol) obtenida en la Etapa 1 y bromuro de propargilo (0,24 ml, 2,81 mmol).N- (4-fluorophenyl) -N- (prop-2-ynyl) pentanoamide (347.60 mg, 57% yield) was obtained by the same method described in Step 2 of Example 45 using the N- (4- fluorophenyl) pentanoamide (500.00 mg, 2.56 mmol) obtained in Step 1 and propargyl bromide (0.24 ml, 2.81 mmol).

RMN de 1H (CDCh, 500 MHz) 8 7,27 (2H, m), 7,14 (2H, m), 4,46 (2H, s), 2,04 (2H, t), 1,55 (2H, m), 1,21 (2H, m), 0,81 (3H, t)1H NMR (CDCh, 500 MHz) 8 7.27 (2H, m), 7.14 (2H, m), 4.46 (2H, s), 2.04 (2H, t), 1.55 ( 2H, m), 1.21 (2H, m), 0.81 (3H, t)

Etapa 3: Preparación de N-(4-fluorofenil)-N-(3-(4-hidroxifenil)prop-2-inil)pentanoamidaStep 3: Preparation of N- (4-fluorophenyl) -N- (3- (4-hydroxyphenyl) prop-2-ynyl) pentanoamide

Se obtuvo N-(4-fluorofenil)-N-(3-(4-hidroxifenil)prop-2-inil)pentanoamida (117,00 mg, rendimiento del 56 %) usando la N-(4-fluorofenil)-N-(prop-2-inil)pentanoamida (300,00 mg, 1,29 mmol) obtenida en la Etapa 3 y 4-yodofenol (140,80 mg, 0,64 mmol).N- (4-fluorophenyl) -N- (3- (4-hydroxyphenyl) prop-2-ynyl) pentanoamide (117.00 mg, 56% yield) was obtained using the N- (4-fluorophenyl) -N- (prop-2-ynyl) pentanoamide (300.00 mg, 1.29 mmol) obtained in Step 3 and 4-iodophenol (140.80 mg, 0.64 mmol).

RMN de 1H (CDCla, 500 MHz) 87,22 (6 H, m), 6,84 (2H, d, J = 8,0 Hz), 4,65 (2H, s), 2,06 (2H, t), 1,55 (2H, m), 1,21 (2H, m), 0,79 (3H, t)1H NMR (CDCla, 500 MHz) 87.22 (6H, m), 6.84 (2H, d, J = 8.0Hz), 4.65 (2H, s), 2.06 (2H, t), 1.55 (2H, m), 1.21 (2H, m), 0.79 (3H, t)

Etapa 4: Preparación de 2-(4-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)fenox¡)acetato de etiloStep 4: Preparation of ethyl 2- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-inl) phenoxy) acetate

Se obtuvo 2-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acetato de etilo (113,00 mg, rendimiento del 81 %) mediante el mismo método descrito en la Etapa 1 del Ejemplo 27 usando la N-(4-fluorofenil)-N-(3-(4-hidroxifenil)prop-2-inil)pentanoamida (110,00 mg, 0,34 mmol) obtenida en la Etapa 3 y bromoacetato de etilo (0,04 ml, 0,37 mmol).Ethyl 2- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetate (113.00 mg, 81% yield) was obtained by the same method described in Step 1 of Example 27 using the N- (4-fluorophenyl) -N- (3- (4-hydroxyphenyl) prop-2-ynyl) pentanoamide (110.00 mg, 0.34 mmol) obtained in Step 3 and bromoacetate of ethyl (0.04 ml, 0.37 mmol).

RMN de 1H (CDCh, 500 MHz) 87,21 (6 H, m), 6,79 (2H, d, J = 9,0 Hz), 4,65 (2H, s), 4,59 (2H, s), 4,24 (2H, m), 2,01 (2H, t), 1,52 (2H, m), 1,21 (5H, m), 0,79 (3H, t)1H NMR (CDCh, 500 MHz) 87.21 (6H, m), 6.79 (2H, d, J = 9.0Hz), 4.65 (2H, s), 4.59 (2H, s), 4.24 (2H, m), 2.01 (2H, t), 1.52 (2H, m), 1.21 (5H, m), 0.79 (3H, t)

Etapa 5: Preparación de ácido 2-(4-(3-(N-(4-fluorofen¡l)pentanoam¡do)prop-1-¡n¡l)fenox¡)acét¡coStep 5: Preparation of 2- (4- (3- (N- (4-fluorophenyl) pentanoamide) prop-1-innl) phenoxy) acetic acid

Se obtuvo ácido 2-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético (25,00 mg, rendimiento del 27 %) mediante el mismo método descrito en la Etapa 5 del Ejemplo 28 usando el 2-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acetato de etilo (100,00 mg, 0,24 mmol) obtenido en la Etapa 4.2- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid (25.00 mg, 27% yield) was obtained by the same method described in Step 5 from Example 28 using ethyl 2- (4- (3- ( N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetate (100.00 mg, 0.24 mmol) obtained in Step 4 .

RMN de 1H (CDCh, 500 MHz) 87,41 (2H, m), 7,26 (4H, m), 6,88 (2H, d, J = 7,0 Hz), 4,66 (2H, s), 4,60 (2H, s), 2,10 (2H, t), 1,52 (2H, m), 1,23 (2H, m), 0,82 (3H, t)1H NMR (CDCh, 500 MHz) 87.41 (2H, m), 7.26 (4H, m), 6.88 (2H, d, J = 7.0 Hz), 4.66 (2H, s ), 4.60 (2H, s), 2.10 (2H, t), 1.52 (2H, m), 1.23 (2H, m), 0.82 (3H, t)

[Ejemplos experimentales][Experimental examples]

Ejemplo experimental 1. Preparación de células que expresan BLT2 o células que no expresan BLT2Experimental Example 1. Preparation of cells that express BLT2 or cells that do not express BLT2

Para este experimento, se prepararon células que no expresan BLT2 y células que expresan BLT2 (células CHO-BLT2) mediante el siguiente método.For this experiment, cells not expressing BLT2 and cells expressing BLT2 (CHO-BLT2 cells) were prepared by the following method.

Se obtuvieron células CHO del Banco de Estirpes Celulares de Corea (KCLB, 10061) y se cultivaron en un medio RPMI 1640 (Invitrogen) que contenía suero bovino fetal al 10 % (FBS; Life Technologies, Inc.), penicilina (50 unidades/ml) y una solución antibiótica y antimicótica (Life Technologies, Inc.) a 37 °C en condiciones de CO2 al 5 %. Las células se dividieron durante 3 días usando Tripsina-EDTA, se mantuvieron en una fase de crecimiento y se lavaron con solución salina tamponada con fosfato (PBS); NaCl 137 mM, KCl 2,7 mM, Na2HPO410 mM, KH2PO4) 2 mM y, después, se añadieron a un medio nuevo, preparando de este modo células que no expresaban BLT2. Además, para preparar clones estables de CHO/BLT2, se transformaron células CHO-K1 con pcDNA3-BLT2 de forma larga que codificaba BLT2 humano marcado con HA y se seleccionaron con 0,4 mg/ml de G418 (Invitrogen, Carlsbad, CA, EE. UU.). Para controlar la expresión de BLT2, los clones seleccionados se analizaron mediante RT-PCR usando un cebador de BLT2 específico de seres humanos y los clones representativos utilizados para el experimento fueron células que expresaban BLT2 (células CHO-BLT2). CHO cells were obtained from the Korea Cell Line Bank (KCLB, 10061) and cultured in RPMI 1640 medium (Invitrogen) containing 10% fetal bovine serum (FBS; Life Technologies, Inc.), penicillin (50 units / ml) and an antibiotic and antifungal solution (Life Technologies, Inc.) at 37 ° C under 5% CO2 conditions. Cells were divided for 3 days using Trypsin-EDTA, kept in a growth phase and washed with phosphate buffered saline (PBS); 137 mM NaCl, 2.7 mM KCl, 10 mM Na2HPO4, 2 mM KH2PO4) and then added to fresh medium, thereby preparing cells that did not express BLT2. In addition, to prepare stable CHO / BLT2 clones, CHO-K1 cells were transformed with long form pcDNA3-BLT2 encoding HA-labeled human BLT2 and selected with 0.4 mg / ml G418 (Invitrogen, Carlsbad, CA, USA). To monitor BLT2 expression, selected clones were analyzed by RT-PCR using a human-specific BLT2 primer and representative clones used for the experiment were BLT2-expressing cells (CHO-BLT2 cells).

Ejemplo experimental 2. Confirmación del efecto inhibidor sobre el crecimiento de células que expresan BLT2 La viabilidad celular de acuerdo con el tratamiento de los compuestos preparados en los ejemplos se midió mediante un método de bromuro de 3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolio (MTT).Experimental Example 2. Confirmation of the inhibitory effect on the growth of cells expressing BLT2 Cell viability according to the treatment of the compounds prepared in the examples was measured by a 3- (4,5-dimethylthiazole-2- yl) -2,5-diphenyltetrazolium (MTT).

Más específicamente, se dispensaron 1 x 104 de cada una de las células que no expresan BLT2 (células CHO-pcDNA3,1) y las células que expresan BLT2 (células CHO-BLT2), que se prepararon en el Ejemplo Experimental 1, en una placa de cultivo de 96 mm y se cultivaron durante 24 horas. Después, el medio de cultivo se retiró, se añadió un medio RPMI sin suero y, después, de dos horas, las células se pretrataron con cada uno de los compuestos preparados en uno de los ejemplos (10 j M), DMSO 10 j M (disolvente compuesto) como control y 1-[5-etil-2-hidroxi-4-[[6-metil-6-(1H-tetrazol-5-il)heptil]oxi]fenil]-etanona 10 j M (LY255283; Cayman) como control positivo durante 1 hora. Posteriormente, después del tratamiento de LTB4 (300 nM), las células se cultivaron durante 24 horas. se añadieron 20 j l de una solución de MTT (5 mg/ml, Sigma-Aldrich) a cada pocillo, las células se cultivaron en una incubadora de CO2 en húmedo a 37 °C durante 4 horas, se retiró el sobrenadante y se añadieron 200 j l de DMSO a cada pocillo para disolver los cristales de formazán insolubles de color violeta. Se midió la absorbancia usando un lector de microplacas (Molecular Devices, Sunnyvale, CA) a 550 nm y la medición se repitió tres veces.More specifically, 1 x 10 4 each of the non-BLT2-expressing cells (CHO-pcDNA3,1 cells) and the BLT2-expressing cells (CHO-BLT2 cells), which were prepared in Experimental Example 1, were dispensed into a 96 mm culture plate and cultured for 24 hours. Then, the culture medium was removed, a serum-free RPMI medium was added and, after two hours, the cells were pretreated with each of the compounds prepared in one of the examples (10 µM), 10 µM DMSO (compound solvent) as a control and 1- [5-ethyl-2-hydroxy-4 - [[6-methyl-6- (1H-tetrazol-5-yl) heptyl] oxy] phenyl] -ethanone 10 jM (LY255283 ; Cayman) as a positive control for 1 hour. Subsequently, after LTB4 treatment (300 nM), the cells were cultured for 24 hours. 20 µl of a MTT solution (5 mg / ml, Sigma-Aldrich) was added to each well, the cells were cultured in a humid CO2 incubator at 37 ° C for 4 hours, the supernatant was removed and 200 μl of DMSO to each well to dissolve the insoluble violet formazan crystals. The absorbance was measured using a microplate reader (Molecular Devices, Sunnyvale, CA) at 550 nm and the measurement was repeated three times.

Como resultado, como se muestra en las FIG. 1A a IE, cuando las células que expresaban BLT2 (células CHO-BLT2) se trataron con LTB4 (300 nM), que es un ligando de BLT2 (DMSO+), se compararon con las células que expresaban BLT2 (células CHO-BLT2) tratadas con etanol (DMSO-), el crecimiento celular aumentó del 20 % al 35 % y, cuando las células que expresaban BLT2 (células CHO-BLT2) se pretrataron con el control positivo LY255283, se compararon con las tratadas con el DMSO de control, se mostró un crecimiento celular de aproximadamente el 90 % y, por tanto, se confirmó que el efecto inhibidor sobre el crecimiento celular se mostraba mediante el tratamiento de los compuestos de los ejemplos. Específicamente, cuando un compuesto de la presente invención (LMT-692, LMT-694, LMT-696 o LMT-1013) se pretrató a 10 j M, en comparación con el DMSO de control, se mostró un crecimiento celular del 88,0 %, 16,7 %, 56,6 % o 96,3 %, respectivamente y, de este modo, se confirmó el efecto inhibidor del crecimiento. Análogamente, los compuestos LMT-837 (65 %), LMT-841 (60 %), LMT-842 (70 %), LMT-883 (99 %), LMT-886 (99 %), LMT-1016 (99 %), LMT-1018 (71,6 %) y LMT-1019 (99 %) también mostraron el efecto inhibidor del crecimiento.As a result, as shown in FIGS. 1A to IE, when cells expressing BLT2 (CHO-BLT2 cells) were treated with LTB4 (300 nM), which is a BLT2 ligand (DMSO +), they were compared to cells expressing BLT2 (CHO-BLT2 cells) treated with ethanol (DMSO-), cell growth increased from 20% to 35% and, when cells expressing BLT2 (CHO-BLT2 cells) were pretreated with the positive control LY255283, they were compared with those treated with the control DMSO, cell growth of about 90% was shown, and therefore it was confirmed that the inhibitory effect on cell growth was shown by treating the compounds of the examples. Specifically, when a compound of the present invention (LMT-692, LMT-694, LMT-696 or LMT-1013) was pretreated at 10 μM, compared to the control DMSO, a cell growth of 88.0 was shown %, 16.7%, 56.6% or 96.3%, respectively, and thus the growth inhibitory effect was confirmed. Similarly, the compounds LMT-837 (65%), LMT-841 (60%), LMT-842 (70%), LMT-883 (99%), LMT-886 (99%), LMT-1016 (99% ), LMT-1018 (71.6%) and LMT-1019 (99%) also showed the growth inhibitory effect.

Los resultados experimentales muestran que los compuestos de la presente invención (LMT-692, LMT-696, LMT-837, LMT-841, LMT-842, LMT-883, LMT-886, LMT-1013, LMT-1016, LMT-1018 y LMT-1019) pueden inhibir el crecimiento celular inducido por BLT2 con una eficiencia excelente y los compuestos pueden usarse como componentes farmacéuticos (moléculas farmacológicas que bloquean BlT2) que pueden usarse como agentes terapéuticos para inhibir el cáncer, el asma o diferentes tipos de enfermedades inflamatorias asociadas a BLT2. Ejemplo experimental 3. Confirmación del efecto inhibidor de la motilidad quimiotáctica dependiente de BLT2 inducida por LTB4The experimental results show that the compounds of the present invention (LMT-692, LMT-696, LMT-837, LMT-841, LMT-842, LMT-883, LMT-886, LMT-1013, LMT-1016, LMT- 1018 and LMT-1019) can inhibit BLT2-induced cell growth with excellent efficiency and the compounds can be used as pharmaceutical components (pharmacological molecules that block BlT2) that can be used as therapeutic agents to inhibit cancer, asthma or different types of inflammatory diseases associated with BLT2. Experimental Example 3. Confirmation of LTB4-induced BLT2-dependent chemotactic motility inhibitory effect

La motilidad quimiotáctica se analizó usando una cámara Transwell que incluía un filtro de policarbonato (tamaño de poro de 8 jm ), Corning Costar) con un diámetro de 6,5 mm. Específicamente, la superficie inferior del filtro se recubrió con fibronectina 10 jg/m l en un medio RPMI 1640 sin suero a 37 °C durante 1 hora. El experimento se realizó colocando el filtro secado y recubierto con medio RPMI 1640 que contenía diversas cantidades de LTB4 en los pocillos inferiores de la cámara Transwell y cargando células c Ho que expresaban BLT1 y BLT2 de forma estable en los pocillos superiores que contenían medio RPMI 1640 sin suero finalmente a 2 x 104 células/100 jl. Para evaluar el efecto de los inhibidores, las células se pretrataron con cada inhibidor durante 30 minutos antes de ser dispensadas. Después de que las células se cultivaran a 37 °C en CO2 al 5 % durante 3 horas, los filtros se fijaron con metanol durante 3 minutos y se tiñeron con hematoxilina y eosina durante 10 minutos. En el experimento, las células eran células que expresaban BLT2 (células CHO-BLT2) y células que expresaban BLT1 (células CHO-BLT1), y se usaron LY255283 y U75302 como controles positivos para cada tipo de células y se usaron ligando de BLT2 LTB4, (300 nM), ligando de BLT1 LTB4 (10 nM) y ácido lisofosfatídico (LPA; 100 nM) como controles comparativos. La motilidad quimiotáctica se analizó cuantitativamente contando las células de la parte inferior del filtro con un microscopio óptico (aumento, 200x). Para cada análisis, se sometieron 6 campos a recuento, cada muestra se analizó dos veces y el análisis se repitió tres veces.Chemotactic motility was analyzed using a Transwell chamber including a polycarbonate filter (8 µm pore size, Corning Costar) with a diameter of 6.5 mm. Specifically, the lower surface of the filter was coated with 10 µg / µl fibronectin in RPMI 1640 medium without serum at 37 ° C for 1 hour. The experiment was performed by placing the dried filter coated with RPMI 1640 medium containing various amounts of LTB4 in the lower wells of the Transwell chamber and loading c Ho cells stably expressing BLT1 and BLT2 in the upper wells containing RPMI 1640 medium. without serum finally at 2 x 104 cells / 100 jl. To evaluate the effect of the inhibitors, the cells were pretreated with each inhibitor for 30 minutes before being dispensed. After the cells were grown at 37 ° C in 5% CO2 for 3 hours, the filters were fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes. In the experiment, the cells were BLT2 expressing cells (CHO-BLT2 cells) and BLT1 expressing cells (CHO-BLT1 cells), and LY255283 and U75302 were used as positive controls for each cell type and BLT2 ligand LTB4 was used. , (300 nM), BLT1 ligand LTB4 (10 nM) and lysophosphatidic acid (LPA; 100 nM) as comparative controls. Chemotactic motility was quantitatively analyzed by counting the cells at the bottom of the filter with an optical microscope (magnification, 200x). For each analysis, 6 fields were counted, each sample was analyzed twice, and the analysis was repeated three times.

Como resultado, como se muestra en las Figuras 2A y 2B y en la Tabla 1, a continuación, en las células que expresaban BLT2 (células CHO-BLT2), a medida que las concentraciones del compuesto de la presente invención (l Mt -692 o LMT-696) aumentaban (10‘4, 10-3, 10'2, 10-1, 1, 10 y 102), la motilidad quimiotáctica de las células CHO-BLT2 se inhibió en condiciones sin suero y las concentraciones inhibidoras del 50 % (CI50) de los compuestos LMT-692 y LMT-696 fueron de 7,566 j M y 2,003 j M, respectivamente.As a result, as shown in Figures 2A and 2B and Table 1 below, in cells expressing BLT2 (CHO-BLT2 cells), as the concentrations of the compound of the present invention (l Mt -692 or LMT-696) increased (10'4, 10-3, 10'2, 10-1, 1, 10 and 102), chemotactic motility of CHO-BLT2 cells was inhibited under serum-free conditions and inhibitory concentrations of the 50% (IC50) of compounds LMT-692 and LMT-696 were 7.566 µM and 2.003 µM, respectively.

[Tabla 1][Table 1]

CI50, j MIC50, j M

receptor LTB4, nM LMT-692 LMT-696LTB4 receiver, nM LMT-692 LMT-696

BLT2 300 7,566 2,003 BLT2 300 7,566 2,003

Además, como se muestra en la Tabla 2, a continuación, se confirmó que, en las células que expresaban BLT2 (células CHO-BLT2), a medida que la concentración del compuesto de la presente invención LMT-1013 aumentaba, la motilidad quimiotáctica de las células CHO-BLT2 se inhibió en condiciones sin suero y la CI50 del compuesto LMT-1013 fue de 62,35 nM.Furthermore, as shown in Table 2 below, it was confirmed that, in cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound of the present invention LMT-1013 increased, the chemotactic motility of CHO-BLT2 cells were inhibited under serum-free conditions and the IC50 of compound LMT-1013 was 62.35 nM.

Análogamente, se confirmó que, en las células que expresaban BLT1 (células CHO-BLT1), a medida aumentaba que la concentración del compuesto de la presente invención LMT-1013, la motilidad quimiotáctica de las células CHO-BLT2 se inhibió en condiciones sin suero y la CI50 del compuesto LMT-1013 fue de 10 pM o más.Similarly, it was confirmed that, in cells expressing BLT1 (CHO-BLT1 cells), as the concentration of the compound of the present invention LMT-1013 increased, the chemotactic motility of CHO-BLT2 cells was inhibited under serum-free conditions. and the IC50 of compound LMT-1013 was 10 pM or more.

[Tabla 21[Table 21

CI50, nMIC50, nM

Receptor LTB4, nM LMT-1013LTB4 Receiver, nM LMT-1013

BLT1 10 > 10 pmBLT1 10> 10 pm

BLT2 300 62,38BLT2 300 62.38

Además, como se muestra en las FIG. 3A y 3B, cuando las células que expresaban BLT2 (células CHO-BLT2) se trataron con el ligando de BLT2 LTB4 (300 nM) (DMSO+), en comparación con las tratadas con etanol (DMSO-), la motilidad quimiotáctica de las células aumentó 2,4 veces y las células pretratadas con LY255283 utilizadas como control positivo (10 pM) presentaron una motilidad quimiotáctica del 90 % en comparación con las células tratadas con el ligando LTB4. Análogamente, se confirmó que, cuando las células que expresaban BLT1 (células CHO-BLT1) se trataron con el ligando LTB4 (10 nM) (DMSO+), en comparación con las tratadas con etanol (DMSO-), la motilidad quimiotáctica de las células aumentó 2,2 veces y las células pretratadas con U75302 utilizadas como control positivo (10 pM) presentaron una motilidad quimiotáctica del 90 % en comparación con las tratadas con el ligando LTB4. Sin embargo, se confirmó que, cuando las células que expresaban BLT2 se pretrataron con el compuesto de la presente invención (LMT-692, l Mt -694 o LMT-696) a 10 pM, en comparación con las tratadas con el ligando LTB4 (DMSO+), la motilidad quimiotáctica se inhibió un 66 %, un 90 % o un 70,3 %, respectivamente, pero las células que expresaban BLT1 (células CHO-BLT1), en comparación con el ligando LTB4 (DMSO+), no mostraron el efecto inhibidor sobre la motilidad quimiotáctica.Furthermore, as shown in FIGS. 3A and 3B, when cells expressing BLT2 (CHO-BLT2 cells) were treated with the BLT2 ligand LTB4 (300 nM) (DMSO +), compared to those treated with ethanol (DMSO-), the chemotactic motility of the cells increased 2.4 times and cells pretreated with LY255283 used as positive control (10 pM) showed a chemotactic motility of 90% compared to cells treated with LTB4 ligand. Similarly, it was confirmed that, when cells expressing BLT1 (CHO-BLT1 cells) were treated with the ligand LTB4 (10 nM) (DMSO +), compared to those treated with ethanol (DMSO-), the chemotactic motility of the cells increased 2.2 times and cells pretreated with U75302 used as positive control (10 pM) showed a chemotactic motility of 90% compared to those treated with LTB4 ligand. However, it was confirmed that, when cells expressing BLT2 were pretreated with the compound of the present invention (LMT-692, 1 Mt -694 or LMT-696) at 10 pM, compared to those treated with the LTB4 ligand ( DMSO +), chemotactic motility was inhibited by 66%, 90% or 70.3%, respectively, but cells expressing BLT1 (CHO-BLT1 cells), compared to LTB4 ligand (DMSO +), did not show the inhibitory effect on chemotactic motility.

Los resultados muestran que, en las células en las que se expresaba BLT2 de forma estable (células CHO-BLT2), la motilidad quimiotáctica aumentó debido al estímulo de LTB4, el compuesto de la presente invención (LMT-692, LMT-696, o LMT-1013) puede inhibir considerablemente la motilidad quimiotáctica y, por tanto, puede utilizarse como componente farmacéutico para inhibir la motilidad quimiotáctica dependiente de BlT2 inducida por LTB4.The results show that, in cells in which BLT2 was stably expressed (CHO-BLT2 cells), chemotactic motility increased due to the stimulation of LTB4, the compound of the present invention (LMT-692, LMT-696, or LMT-1013) can significantly inhibit chemotactic motility and therefore can be used as a pharmaceutical component to inhibit LTB4-induced BlT2-dependent chemotactic motility.

Ejemplo experimental 4. Confirmación del efecto inhibidor de la unión de LTB4 y BLT2Experimental Example 4. Confirmation of the inhibitory effect on the binding of LTB4 and BLT2

La inhibición de la unión de LTB4 y BLT2 (afinidad de unión a ligando) se analizó usando tritio radioactivo LTB4 marcado con (3H) ([3H]LTB4, ARC; actividad específica 160,0 Ci/mmol). Después de que se colocaran 2 x 106 células CHO-BLT2 en una placa de cultivo de 100 mm y se cultivaran durante 48 horas, se realizó un método experimental de la siguiente manera: Las células recogidas se trataron usando un homogeneizador un total de cinco veces durante 1 minuto cada una para separar las proteínas de la membrana celular. Después, las células se sometieron a centrifugación a 4 °C y 45.000 rpm durante 40 minutos para recoger solamente las proteínas de la membrana celular y, de este modo, se cuantificó la concentración de proteínas de 40 pg/45 pl. Cuando se trataron proteínas de membrana celular que contenían BLT2, que se cuantificaron de la misma manera, con la misma cantidad de [3H]LTB4 (5 nM) y después una concentración diferente (10‘9, 10'8, 10'7, 10'6 o 10'5 M) de un compuesto, se midió el grado de inhibición de la unión de LTB4 marcado con tritio y BLT2 usando un contador de centelleo de líquido Hidex 300sL.Inhibition of LTB4 and BLT2 binding (ligand binding affinity) was tested using (3H) -labeled radioactive tritium LTB4 ([3H] LTB4, ARC; specific activity 160.0 Ci / mmol). After 2 x 10 6 CHO-BLT2 cells were placed in a 100 mm culture plate and cultured for 48 hours, an experimental method was performed as follows: The collected cells were treated using a homogenizer a total of five times for 1 minute each to separate the proteins from the cell membrane. The cells were then subjected to centrifugation at 4 ° C and 45,000 rpm for 40 minutes to collect only the cell membrane proteins, and thus the protein concentration of 40 pg / 45 µl was quantified. When cell membrane proteins containing BLT2 were treated, which were quantified in the same way, with the same amount of [3H] LTB4 (5 nM) and then a different concentration (10'9, 10'8, 10'7, 10.6 or 10.5 M) of a compound, the degree of inhibition of the binding of tritium-labeled LTB4 and BLT2 was measured using a Hidex 300sL liquid scintillation counter.

Como resultado, como se muestra en las FIG. 4A y 4B, se confirmó que, en las células que expresaban BLT2 (células CHO-BLT2), a medida que la concentración del compuesto de la presente invención (LMT-696 o LMT-1013) aumentaba (10‘9, 10'8, 10'7, 10'6 y 10'5M), se inhibió la unión de LTB4 y BLT2 y la CI50 de los compuestos LMT-696 y LMT-1013 fue de 5,6 nM y 30,74 nM, respectivamente.As a result, as shown in FIGS. 4A and 4B, it was confirmed that, in cells expressing BLT2 (CHO-BLT2 cells), as the concentration of the compound of the present invention (LMT-696 or LMT-1013) increased (10'9, 10'8 , 10.7, 10.6 and 10.5M), the binding of LTB4 and BLT2 was inhibited and the IC50 of compounds LMT-696 and LMT-1013 was 5.6 nM and 30.74 nM, respectively.

Ejemplo experimental 5. Confirmación del efecto antineoplásico debido a la inhibición de BLT2Experimental Example 5. Confirmation of the antineoplastic effect due to inhibition of BLT2

Los inventores han informado a partir de investigaciones anteriores que BLT2 regula la generación de especies de oxígeno reactivas (ROS) intracelulares y una citocina interleucina-8 (lL-8) en células de cáncer de mama, tales como las células MDA-MB-231 y MDA-MB-453, dando como resultado el control de la invasión y la metástasis de las células cancerosas. En consecuencia, se confirmó que la generación de ROS y la expresión de IL-8 se inhibieron de acuerdo con el tratamiento con el compuesto de la presente invención en células de cáncer de mama MDA-MB-231 y MDA-MB-453.The inventors have reported from previous research that BLT2 regulates the generation of intracellular reactive oxygen species (ROS) and an interleukin-8 (IL-8) cytokine in breast cancer cells, such as MDA-MB-231 cells. and MDA-MB-453, resulting in the control of cancer cell invasion and metastasis. Consequently, it was confirmed that ROS generation and IL-8 expression were inhibited according to the treatment with the compound of the present invention in MDA-MB-231 and MDA-MB-453 breast cancer cells.

5-1. Preparación de células de cáncer de mama5-1. Breast Cancer Cell Preparation

Las células de cáncer de mama tales como las células MDA-MB-231 se obtuvieron del Banco de Estirpes Celulares de Corea (Seúl, Corea) y las células MDA-MB-435 fueron proporcionadas por J. H. Lee (Centro Médico Asan, Seúl, Corea). Estas células se cultivaron en un medio RPMI 1640 (Invitrogen) que contenía FBS al 10 % (Life Technologies, Inc.), penicilina al 1 % (50 unidades/ml) y una solución antibiótica y antimicótica (Life Technologies, Inc.) a 37 °C en condiciones de CO2 al 5 %.Breast cancer cells such as MDA-MB-231 cells were obtained from Korea Cell Line Bank (Seoul, Korea) and MDA-MB-435 cells were provided by JH Lee (Asan Medical Center, Seoul, Korea). These cells were cultured in RPMI 1640 medium (Invitrogen) containing 10 % FBS (Life Technologies, Inc.), 1% penicillin (50 units / ml), and an antibiotic and antifungal solution (Life Technologies, Inc.) to 37 ° C under 5% CO2 conditions.

5-2. Confirmación del efecto inhibidor sobre la generación de ROS intracelulares5-2. Confirmation of the inhibitory effect on the generation of intracellular ROS

La ROS intracelular (H2O2) generada de acuerdo con el tratamiento con el compuesto de la presente invención (LMT-696) se midió en función de la fluorescencia de DCF. Específicamente, antes de la medición de ROS, se cultivaron 2 x 105 células en pocillos de 60 mm y se cultivaron en un medio RPMI 1640 complementado con FBS durante 24 horas. Para evaluar el efecto del compuesto de la presente invención, las células se trataron con el compuesto (LMT-696) durante 30 minutos. Para medir la ROS intracelular, las células se cultivaron con 20 pM de un material fluorescente sensible al H2O2, tal como H2DCFDA [Molecular Probes (Eugene, OR)], a 37 °C en una incubadora de CO2 oscura y humidificada durante 20 minutos. El H2DCFDA se hidrolizó a DCF en las células y se oxidó a DCF presentando una fluorescencia alta en presencia de H2O2 y, por tanto, la cantidad de ROS se midió usando dicha propiedad. Además, para confirmar la generación de ROS usando un detector, las células se recogieron usando tripsina-EDTA y se resuspendieron en RPMI 1640 sin suero, sin rojo de fenol. Se midió el grado de fluorescencia de DCF con longitudes de onda de excitación y emisión a 488 y 530 nm, respectivamente, usando un citómetro de flujo FACS Calibur (Becton Dickinson, NJ).Intracellular ROS (H2O2) generated according to treatment with the compound of the present invention (LMT-696) was measured as a function of DCF fluorescence. Specifically, prior to ROS measurement, 2 x 10 5 cells were grown in 60 mm wells and cultured in RPMI 1640 medium supplemented with FBS for 24 hours. To evaluate the effect of the compound of the present invention, cells were treated with the compound (LMT-696) for 30 minutes. To measure intracellular ROS, cells were cultured with 20 pM of a H2O2 sensitive fluorescent material, such as H2DCFDA [Molecular Probes (Eugene, OR)], at 37 ° C in a humidified, dark CO2 incubator for 20 minutes. H2DCFDA was hydrolyzed to DCF in cells and oxidized to DCF showing high fluorescence in the presence of H2O2 and therefore the amount of ROS was measured using this property. In addition, to confirm ROS generation using a detector, cells were harvested using trypsin-EDTA and resuspended in RPMI 1640 without serum, without phenol red. The degree of DCF fluorescence was measured with excitation and emission wavelengths at 488 and 530 nm, respectively, using a FACS Calibur flow cytometer (Becton Dickinson, NJ).

Como resultado, como se muestra en las FIG. 5A y 5B, se confirmó que, cuando se trataron con el compuesto de la presente invención (LMT-696), las células de cáncer de mama tales como las células MDA-MB-231 y MDA-MB-435 presentaron una inhibición significativa de la generación de ROS.As a result, as shown in FIGS. 5A and 5B, it was confirmed that, when treated with the compound of the present invention (LMT-696), breast cancer cells such as MDA-MB-231 and MDA-MB-435 cells showed significant inhibition of the generation of ROS.

5-3. Confirmación del efecto inhibidor sobre la expresión de IL-85-3. Confirmation of the inhibitory effect on IL-8 expression

Para confirmar la expresión de IL-8 de acuerdo con el tratamiento con el compuesto de la presente invención, se aisló ARN total de las células usando Easy Blue (Intron, Sungnam, Corea) y se cuantificó mediante absorbencia a 260 nm. Se sintetizó ADN complementario (ADNc) con el ARN (1,25 pg) a través de transcripción inversa usando una técnica de reacción en cadena de la polimerasa (PCR). Se determinó el nivel de expresión usando cebadores que se unen específicamente a IL-8 y gliceraldehído-3-fosfato deshidrogenasa (GAPDH).To confirm IL-8 expression according to treatment with the compound of the present invention, total RNA was isolated from cells using Easy Blue (Intron, Sungnam, Korea) and quantitated by absorbance at 260 nm. Complementary DNA (cDNA) was synthesized with RNA (1.25 pg) via reverse transcription using a polymerase chain reaction (PCR) technique. The level of expression was determined using primers that specifically bind IL-8 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Como resultado, como se muestra en las FIG. 6A y 6B, se confirmó que, cuando se trataron con el compuesto de la presente invención (LMT-696), las células de cáncer de mama, tales como las células MDA-MB-231 y MDA-MB-435, presentaron un nivel de expresión de IL-8 significativamente inhibido.As a result, as shown in FIGS. 6A and 6B, it was confirmed that, when treated with the compound of the present invention (LMT-696), breast cancer cells, such as MDA-MB-231 and MDA-MB-435 cells, presented a level IL-8 expression significantly inhibited.

5-4. Confirmación del efecto inhibidor sobre la invasión de células de cáncer de mama5-4. Confirmation of the inhibitory effect on the invasion of breast cancer cells

Para detectar la invasión de células de cáncer de mama de acuerdo con el tratamiento con el compuesto de la presente invención, se usaron cámaras de invasión BioCoat Matrigel Invasion Chambers (BD Biosciences, Bedford, MA). Se recogieron 5 x 104 células de cáncer de mama con tripsina-EDTA, se resuspendieron en RPMI 1640 que contenía suero al 0,5 % y se transfirieron a insertos de Matrigel. Se añadió RPMI 1640 que contenía suero al cinco por ciento a la cámara inferior y las células se cultivaron a 37 °C durante 36 horas. Cada filtro se fijó con metanol durante 3 minutos y se tiñó con hematoxilina y eosina durante 10 minutos. La invasividad de las células cancerosas se cuantificó mediante recuentos de células en la parte inferior del filtro con un microscopio óptico (aumento, 200x). En cada análisis, se cuantificaron 6 campos. Cada muestra se analizó dos veces y el análisis se repitió tres veces. To detect invasion of breast cancer cells according to treatment with the compound of the present invention, BioCoat Matrigel Invasion Chambers (BD Biosciences, Bedford, MA) were used. 5 x 104 breast cancer cells were harvested with trypsin-EDTA, resuspended in RPMI 1640 containing 0.5% serum and transferred to Matrigel inserts. RPMI 1640 containing five percent serum was added to the lower chamber and the cells were cultured at 37 ° C for 36 hours. Each filter was fixed with methanol for 3 minutes and stained with hematoxylin and eosin for 10 minutes. Cancer cell invasiveness was quantified by cell counts on the bottom of the filter under a light microscope (magnification, 200x). In each analysis, 6 fields were quantified. Each sample was analyzed twice and the analysis was repeated three times.

Como resultado, como se muestra en las FIG. 7A y 7B, cuando se trataron con el compuesto de la presente invención (LMT-696), se confirmó que la invasión de células cancerosas se inhibió un 70 % para las células MDA-MB-231 y se inhibió un 56 % para las células MDA-MB-435.As a result, as shown in FIGS. 7A and 7B, when treated with the compound of the present invention (LMT-696), it was confirmed that cancer cell invasion was 70% inhibited for MDA-MB-231 cells and 56% inhibited for cells. MDA-MB-435.

5-5. Confirmación del efecto inhibidor sobre la metástasis de células de cáncer de mama5-5. Confirmation of the inhibitory effect on breast cancer cell metastasis

El Comité de Ética de la Universidad de Corea aprobó un experimento para la metástasis de células de cáncer de mama de acuerdo con el tratamiento con el compuesto de la presente invención y todos los animales de experimentación utilizados en este experimento se trataron de acuerdo con las directrices aprobadas del Comité de Cuidado y Uso de Animales de la Universidad de Corea. Se inyectaron ratones desnudos hembra de seis semanas (Charles River, Wilmington, MA) con células cancerosas para confirmar la metástasis de las células cancerosas. Las células de cáncer de mama se pretrataron con el compuesto de la presente invención (LMT-696, 10 pM), LY255283, U75302 y DMSO y, 24 horas después, se recogieron con tripsina-EDTA, se resuspendieron en PBS y, después, se inyectaron por vía intraperitoneal 2 x 106 de las células de cáncer de mama en ratones anestesiados con zoletil (50 mg/kg). Después de cinco días, el compuesto de la presente invención (LMT-696; 2,5 mg/kg), LY255283 (2,5 mg/kg), U75302 (0,25 mg/kg) y DMSO se inyectaron por vía intraperitoneal tres veces cada cinco días. 15 semanas después de la inyección de las células de cáncer de mama, los ratones se disecaron para observar la metástasis de las células cancerosas.The Ethics Committee of the University of Korea approved an experiment for the metastasis of breast cancer cells according to the treatment with the compound of the present invention and all the experimental animals used in this experiment were treated according to the guidelines approved by the Animal Care and Use Committee of the University of Korea. Six week old female nude mice (Charles River, Wilmington, MA) were injected with cancer cells to confirm cancer cell metastasis. Breast cancer cells were pretreated with the compound of the present invention (LMT-696, 10 pM), LY255283, U75302 and DMSO and, 24 hours later, they were collected with trypsin-EDTA, resuspended in PBS and then, 2 x 10 6 breast cancer cells were injected intraperitoneally into mice anesthetized with zolethyl (50 mg / kg). After five days, the compound of the present invention (LMT-696; 2.5 mg / kg), LY255283 (2.5 mg / kg), U75302 (0.25 mg / kg) and DMSO were injected intraperitoneally three times every five days. 15 weeks after the injection of the breast cancer cells, the mice were dissected to observe the metastasis of the cancer cells.

Como resultado, como se muestra en las FIG. 8, 9A y 9B, se confirmó que la metástasis de las células cancerosas (MDA-MB-231) se inhibió un 40 % mediante el tratamiento con el compuesto de la presente invención (LMT-696), se inhibió un 36 % mediante el tratamiento con un control positivo LY255283, en comparación con el control, y no se inhibió mediante el tratamiento con U75302.As a result, as shown in FIGS. 8, 9A and 9B, it was confirmed that cancer cell metastasis (MDA-MB-231) was inhibited by 40 % by treatment with the compound of the present invention (LMT-696), it was inhibited by 36% by treatment with a positive control LY255283, compared to the control, and not it was inhibited by treatment with U75302.

Los resultados muestran que el compuesto de la presente invención (LMT-696) puede inhibir la generación de ROS intracelulares e IL-8 de las células cancerosas y, por tanto, puede inhibir la invasividad y la metástasis de las células cancerosas y, por tanto, el compuesto puede usarse como componente farmacéutico que tiene una eficiencia antineoplásica excelente.The results show that the compound of the present invention (LMT-696) can inhibit the generation of intracellular ROS and IL-8 from cancer cells and, therefore, can inhibit the invasiveness and metastasis of cancer cells and therefore , the compound can be used as a pharmaceutical component having excellent antineoplastic efficiency.

Ejemplo experimental 6. Confirmación del efecto antiasmático por la inhibición de LBT2Experimental example 6. Confirmation of the antiasthmatic effect by the inhibition of LBT2

Los mastocitos desempeñan una función fundamental en la reacción inicial al asma y, cuando un alérgeno entra en el cuerpo desde el exterior a través de una vía respiratoria, los mastocitos se activan, secretando de este modo diversas citocinas (interleucina-4 e interleucina-13). Debido a las citocinas, se produce el influjo de células inflamatorias, la generación de moco y la contracción de las vías respiratorias. Los inventores usaron ratones BALB/c hembra de 7 semanas de edad (18 a 20 g) proporcionados por Orient (Seoungnam, Corea) para el experimento para confirmar el efecto antiasmático y, después, se indujo el asma en los ratones. El primer día y el día 14o, se incluyeron 2,5 mg de un adyuvante, gel de hidróxido de aluminio (alumbre; Pierce, Rockford, IL), en 20 mg de ovoalbúmina (OVA) para sensibilizar por vía intraperitoneal ratones hembra C57BL/6. Los días 21o, 22o y 23o de dos sensibilizaciones iniciales, se pulverizó OVA al 1 % en los ratones usando un nebulizador ultrasónico. El compuesto de la presente invención (LMT-696; 5 mg/kg), LY255283 (5 mg/kg, Caimán) o DMSO se inyectaron por vía intraperitoneal en la 1 hora anterior a la pulverización de OVA al 1 %. El día 24o de la sensibilización inicial, se detectó hipersensibilidad de las vías respiratorias (HSVR) y, el día 25o, los ratones se disecaron para observar los fenotipos de asma, por ejemplo, la expresión de la citocina inflamatoria IL-4 y el influjo de células inflamatorias (neutrófilos). En el caso de modelos en animales de asma grave inducida por lipopolisacáridos (LPS), los días 0, 1o, 2o y 7o, se inyectaron por vía intranasal 75 |jg de OVA y 1 mg de LPS en ratones Balb/c para la sensibilización. Los días 14o, 15o, 21o y 22o, se inyectaron 50 jg de OVA en la nariz para una exposición. El compuesto de la presente invención (LMT-1013) (1, 3, 10 o 30 mg/kg), montelukast (10 mg/kg, DRS) o un tampón de control (DMA al 10 %, Tween 80 al 5 %, salmuera al 85 %) se administraron una hora antes de la exposición mediante la inyección de 50 jg de OVA en la nariz. El día 23o de la sensibilización inicial, se detectó HSVR y, el día 24o, los ratones se disecaron para observar un fenotipo de asma grave, por ejemplo, el influjo de las células inflamatorias (neutrófilos). Además, la detección de HSVR se realizó después de que se administrara a los ratones un constrictor de las vías respiratorias, metacolina (de 6,25 a 50 mg/ml dependiendo de las condiciones). La administración del constrictor de las vías respiratorias se realizó mediante la pulverización a través de una entrada de la cámara usando un nebulizador ultrasónico durante 3 minutos. La HSVR se analizó usando una pausa potenciada como indicador del fenómeno del asma. Se cuantificaron recuentos de células de líquido de lavado broncoalveolar mediante el recuento de células con un microscopio óptico (aumento, 200x). En cada análisis, se sometieron 4 campos a recuento, cada muestra se analizó dos veces y el análisis se repitió tres veces.Mast cells play a key role in the initial reaction to asthma, and when an allergen enters the body from the outside through an airway, mast cells are activated, thereby secreting various cytokines (interleukin-4 and interleukin-13 ). Due to cytokines, the influx of inflammatory cells, the generation of mucus and the contraction of the airways occurs. The inventors used 7-week-old female BALB / c mice (18-20 g) provided by Orient (Seoungnam, Korea) for the experiment to confirm the anti-asthmatic effect, and then asthma was induced in the mice. On day 1 and day 14, 2.5 mg of an adjuvant, aluminum hydroxide gel (alum; Pierce, Rockford, IL), was included in 20 mg of ovalbumin (OVA) to sensitize female C57BL / female mice intraperitoneally. 6. On the 21st, 22nd and 23rd days of two initial sensitizations, 1% OVA was sprayed on the mice using an ultrasonic nebulizer. The compound of the present invention (LMT-696; 5 mg / kg), LY255283 (5 mg / kg, Cayman) or DMSO were injected intraperitoneally within 1 hour prior to the 1% OVA spray. On day 24 of initial sensitization, airway hypersensitivity (HSVR) was detected and, on day 25, mice were dissected to observe asthma phenotypes, for example, expression of the inflammatory cytokine IL-4 and the influx inflammatory cells (neutrophils). In the case of animal models of severe lipopolysaccharide (LPS) -induced asthma, on days 0, 1, 2 and 7, 75 µg of OVA and 1 mg of LPS were injected intranasally into Balb / c mice for sensitization. . On days 14, 15, 21 and 22, 50 µg of OVA was injected into the nose for one challenge. The compound of the present invention (LMT-1013) (1, 3, 10 or 30 mg / kg), montelukast (10 mg / kg, DRS) or a control buffer (10% DMA, 5% Tween 80, 85% brine) were administered one hour before challenge by injecting 50 µg of OVA into the nose. On the 23rd day of initial priming, HSVR was detected and, on the 24th day, the mice were dissected to observe a severe asthma phenotype, for example, the influx of inflammatory cells (neutrophils). Furthermore, HSVR detection was performed after mice were administered an airway constrictor, methacholine (6.25 to 50 mg / ml depending on conditions). Administration of the airway constrictor was accomplished by spraying through a chamber inlet using an ultrasonic nebulizer for 3 minutes. HSVR was analyzed using an enhanced pause as an indicator of the asthma phenomenon. Bronchoalveolar lavage fluid cell counts were quantified by cell counting under a light microscope (magnification, 200x). In each analysis, 4 fields were counted, each sample was analyzed twice, and the analysis was repeated three times.

Además, como se muestra en las FIG. 10 y 11, se confirmó que, cuando se pretrató con un control positivo, LY255283, a 10 jM , la HSVR de los ratones en los que se indujo asma grave mediante la administración de 50 mg/ml de un constrictor de las vías respiratorias se redujo un 69,2 % y la generación de IL-4 en las células aisladas de la cavidad abdominal de los ratones se redujo un 67,2 %. Además, cuando se pretrató con el compuesto de la presente invención (LMT-696) a 10 jM , la HSVR de los ratones en los que se indujo asma grave mediante la administración de 50 mg/ml de un constrictor de las vías respiratorias se redujo un 70 % y la generación de IL-4 de células aisladas de la cavidad abdominal de los ratones se redujo un 70 %.Furthermore, as shown in FIGS. 10 and 11, it was confirmed that, when pretreated with a positive control, LY255283, at 10 jM, the HSVR of the mice in which severe asthma was induced by the administration of 50 mg / ml of an airway constrictor was it was reduced by 69.2% and the generation of IL-4 in cells isolated from the abdominal cavity of mice was reduced by 67.2%. Furthermore, when pretreated with the compound of the present invention (LMT-696) at 10 jM, the HSVR of the mice in which severe asthma was induced by the administration of 50 mg / ml of an airway constrictor was reduced 70% and the generation of IL-4 from cells isolated from the abdominal cavity of mice was reduced by 70%.

Además, como se muestra en la FIG. 12, en los ratones con asma inducida (OVA+LPS), en comparación con los ratones en los que no se indujo asma (Normales), la HSVR aumentó 13 veces y se confirmó que, cuando se pretrataron con el compuesto de la presente invención (LMT-1013) a 1, 3, 10 y 30 mg/kg, los ratones con asma inducida (OVA+LPS), en comparación con ratones a los que se les administraron 50 mg/ml del constrictor de las vías respiratorias, la HSVR se redujo un 48,6 %, un 52,9 %, un 83,2 % y un 87,3 %, respectivamente. Por el contrario, se confirmó que, en comparación con los ratones a los que se les administraron 50 mg/ml del constrictor de las vías respiratorias, cuando se pretrataron con un material comparativo, montelukast, a 10 mg/kg, la HSVR de los ratones con asma inducida (OVA+LPS) se redujo un 64 %.Furthermore, as shown in FIG. 12, in the mice with induced asthma (OVA + LPS), compared to the mice in which asthma was not induced (Normal), the HSVR increased 13 times and it was confirmed that, when they were pretreated with the compound of the present invention (LMT-1013) at 1, 3, 10 and 30 mg / kg, the mice with induced asthma (OVA + LPS), compared to mice given 50 mg / ml of the airway constrictor, the HSVR decreased 48.6%, 52.9%, 83.2%, and 87.3%, respectively. In contrast, it was confirmed that, compared to mice given 50 mg / ml of the airway constrictor, when pretreated with a comparative material, montelukast, at 10 mg / kg, the HSVR of the mice with induced asthma (OVA + LPS) was reduced by 64%.

Además, como se muestra en las FIG. 13A, 13B y 13C, se confirmó que, cuando se pretrató con el compuesto de la presente invención (LMT-1013) a 1 y 10 mg/kg, en los ratones con asma inducida (OVA+LPS), se redujeron las células y los neutrófilos totales que entraban en la cavidad abdominal de los ratones y, en particular, las células inmunitarias, es decir, los neutrófilos, se redujeron un 51,6 % y un 90,3 %, respectivamente.Furthermore, as shown in FIGS. 13A, 13B and 13C, it was confirmed that, when pretreated with the compound of the present invention (LMT-1013) at 1 and 10 mg / kg, in the mice with induced asthma (OVA + LPS), the cells were reduced and total neutrophils entering the abdominal cavity of mice and, in particular, immune cells, ie neutrophils, were reduced by 51.6% and 90.3%, respectively.

Adicionalmente, como se muestra en las FIG. 14A y 14B, se confirmó que, cuando se pretrató con el compuesto de la presente invención (LMT-1013) a 1, 3, 10 y 30 mg/kg, en los ratones con asma inducida (OVA+LPS), se redujeron las células y los neutrófilos totales que entraban en la cavidad abdominal de los ratones y, en particular, los neutrófilos se redujeron un 42,2 %, un 48,8 %, un 71,8 % y un 88,3 %, respectivamente. Por el contrario, se confirmó que, cuando se pretrató con el material comparativo montelukast a 10 mg/kg, las células inmunitarias, es decir, los neutrófilos, que entraban en la cavidad abdominal de los ratones no se redujeron.Additionally, as shown in FIGS. 14A and 14B, it was confirmed that, when pretreated with the compound of the present invention (LMT-1013) at 1, 3, 10 and 30 mg / kg, in the mice with induced asthma (OVA + LPS), the cells and total neutrophils entering the abdominal cavity of mice and, in particular, neutrophils were reduced by 42.2%, 48.8%, 71.8% and 88.3%, respectively. On the contrary, it was confirmed that, when pretreated with the comparative montelukast material at 10 mg / kg, the immune cells, that is, the Neutrophils, which entered the abdominal cavity of the mice, were not reduced.

Los resultados mostraron que los compuestos de la presente invención (LMT-696 y LMT-1013) inhibieron la HSVR en modelos en animales de asma, el compuesto LMT-696 inhibió la generación de una citocina inflamatoria IL-4 y el compuesto LMT-1013 inhibió el influjo de células inmunitarias en la cavidad abdominal, dando como resultado el alivio de los síntomas del asma y, por tanto, estos compuestos pueden usarse como componente farmacéutico que tiene un efecto antiasmático.The results showed that the compounds of the present invention (LMT-696 and LMT-1013) inhibited HSVR in animal models of asthma, the compound LMT-696 inhibited the generation of an inflammatory cytokine IL-4 and the compound LMT-1013 inhibited the influx of immune cells into the abdominal cavity, resulting in relief of asthma symptoms, and therefore these compounds can be used as a pharmaceutical component having an anti-asthma effect.

[Disponibilidad industrial][Industrial availability]

La presente invención se refiere a un compuesto novedoso que tiene una actividad inhibidora de BLT2 y una composición farmacéutica para prevenir o tratar una enfermedad inflamatoria, que incluye el compuesto. Los inventores identificaron un compuesto novedoso que contenía actividad inhibidora de BTL2 para resolver los problemas de los compuestos convencionales que se habían diseñado para tratar una enfermedad inflamatoria; por ejemplo, la inestabilidad en organismos vivos y la dificultad de la producción en masa. Además, se confirmó experimentalmente que el presente compuesto novedoso tenía un efecto excelente sobre la potenciación de la muerte de células cancerosas, sobre la inhibición de la metástasis y la movilidad quimiotáctica y sobre la actividad antiasmática. Por tanto, el presente compuesto novedoso puede usarse como un componente farmacéutico muy eficaz para el tratamiento de las enfermedades relacionadas con la inflamación. The present invention relates to a novel compound having a BLT2 inhibitory activity and a pharmaceutical composition for preventing or treating an inflammatory disease, which includes the compound. The inventors identified a novel compound containing BTL2 inhibitory activity to solve the problems of conventional compounds that had been designed to treat inflammatory disease; for example, instability in living organisms and the difficulty of mass production. Furthermore, it was experimentally confirmed that the present novel compound had an excellent effect on enhancing cancer cell death, inhibiting metastasis and chemotactic mobility, and anti-asthma activity. Therefore, the present novel compound can be used as a highly effective pharmaceutical component for the treatment of inflammation-related diseases.

Claims (4)

REIVINDICACIONES 1. Un compuesto representado por la Fórmula 1, a continuación, o una sal farmacéuticamente aceptable del mismo:1. A compound represented by Formula 1, below, or a pharmaceutically acceptable salt thereof:
Figure imgf000029_0001
Figure imgf000029_0001
 En la Fórmula 1,In Formula 1, R1 es alquilo C1 a C10,R1 is C1 to C10 alkyl, R2 esR2 is
Figure imgf000029_0002
Figure imgf000029_0002
 Rc es Rc is
Figure imgf000030_0001
Figure imgf000030_0001
 Rd es hidrógeno oRd is hydrogen or
Figure imgf000030_0002
Figure imgf000030_0002
 Re esRe is
Figure imgf000030_0003
Figure imgf000030_0003
 yY R3 es hidrógeno o flúor.R3 is hydrogen or fluorine. 2. El compuesto de la reivindicación 1, en donde el compuesto representado por la Fórmula 1 se selecciona del grupo que consiste en los siguientes compuestos:2. The compound of claim 1, wherein the compound represented by Formula 1 is selected from the group consisting of the following compounds: 4-(4-(3-(N-fenilpentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-fenil-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-etilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2 -inil)-N-fenilpentanoamida; N-(3-(4-(4-(2-hidroxietil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(ciclopropilmetil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-ciclohexilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(4-(ciclohexilmetil)piperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-isobutilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-fenil-N-(3-(4-(4-(prop-2-inil)piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(4-cianopiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(3-fluorofenil)-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-fluorofenil)-N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; 4-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(4-fluorofenil)-N-(3-(4-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(4-fluorofenil)-N-(3-(4-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-(morfolin-4-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-fenil-N-(3-(4-(piperidin-1-carbonil)fenil)prop-2-inil)pentanoamida; N,N-dietil-4-(3-(N-fenilpentanoamido)prop-1-inil)benzamida; N-fenil-N-(3-(3-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(3-(4-metilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(3-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(3-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)benzoil)piperazin-1-carboxilato de ferc-butilo; N-(4-fluorofenil)-N-(3-(3-(piperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(4-fluorofenil)-N-(3-(3-(4-isopropilpiperazin-1-carbonil)fenil)prop-2-inil)pentanoamida; N-(3-(4-hidroxifenil)prop-2-inil)-N-fenilpentanoamida; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-inil)fenoxi)acético; 4-(5-(3-((N-fenilpentanoamido)prop-1-in-1-il)picolinoil)piperazin-1-carboxilato de ferc-butilo; N-fenil-N-(3-(6-(piperazin-1-carbonil)piridin-3-il)prop-2-in-1-il)pentanoamida; N-(3-(6-isopropilpiperazin-1-carbonil)piridin-3-il)prop-2-in-1-il)pentanoamida; N,N-dietil-4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-in-1-il)benzamida; N,N-dietil-4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-in-1-il)benzamida; N-(3-(4-(N,N-dietilsulfamoil)fenil)prop-2-inil)-N-fenilpentanoamida; N-(3-(4-(N-isopropilsulfamoil)fenil)prop-2-inil)-N-fenilpentanoamida; 4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzoato de fercbutilo; ácido 4-(3-(N-fenilpentanoamido)pro-1-in-1-il)benzoico; N-etil-4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamida; N-(2-(dietilamino)etil)-4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamida; 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)acetato de etilo; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)acético; 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)propanoato de metilo; ácido 2-(4-(3-(N-fenilpentanoamido)prop-1-in-1-il)benzamido)propiónico; ácido 2-(4-(3-(N-(3-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético; y ácido 2-(4-(3-(N-(4-fluorofenil)pentanoamido)prop-1-inil)fenoxi)acético.Tert-Butyl 4- (4- (3- (N-phenylpentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N-phenyl-N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-ethylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2 -inyl) -N-phenylpentanoamide; N- (3- (4- (4- (2-hydroxyethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (cyclopropylmethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentaneamide; N- (3- (4- (4-cyclohexylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (4- (cyclohexylmethyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4-isobutylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N-phenyl-N- (3- (4- (4- (prop-2-ynyl) piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (4-cyanopiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Tert-Butyl 4- (4- (3- (N- (3-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (3-fluorophenyl) -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3-fluorophenyl) -N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; Tert-Butyl 4- (4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (4-fluorophenyl) -N- (3- (4- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (4-fluorophenyl) -N- (3- (4- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4- (morpholin-4-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N-phenyl-N- (3- (4- (piperidine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N, N-diethyl-4- (3- (N-phenylpentaneamido) prop-1-ynyl) benzamide; N-phenyl-N- (3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (3- (4-methylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Tert-Butyl 4- (3- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) benzoyl) piperazine-1-carboxylate; N- (4-fluorophenyl) -N- (3- (3- (piperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (4-fluorophenyl) -N- (3- (3- (4-isopropylpiperazine-1-carbonyl) phenyl) prop-2-ynyl) pentanoamide; N- (3- (4-hydroxyphenyl) prop-2-ynyl) -N-phenylpentanoamide; 2- (4- (3- (N-phenylpentanoamido) prop-1-ynyl) phenoxy) acetic acid; Tert-Butyl 4- (5- (3 - ((N-phenylpentanoamido) prop-1-in-1-yl) picolinoyl) piperazine-1-carboxylate; N-phenyl-N- (3- (6- (piperazin -1-carbonyl) pyridin-3-yl) prop-2-in-1-yl) pentanoamide; N- (3- (6-isopropylpiperazine-1-carbonyl) pyridin-3-yl) prop-2-in-1 -il) pentanoamide; N, N-diethyl-4- ( 3- ( N- ( 3- fluorophenyl) pentanoamido) prop-1-yn-1-yl) benzamide; N, N-diethyl-4- (3- (N- (4-fluorophenyl) pentanoamido) prop-1-yn-1-yl) benzamide; N- (3- (4- (N, N-diethylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; N- (3- (4- (N-isopropylsulfamoyl) phenyl) prop-2-ynyl) -N-phenylpentanoamide; Fercbutyl 4- (3- (N-phenylpentanoamido) prop-1-in-1-yl) benzoate; 4- (3- (N-phenylpentanoamido) pro-1-yn-1-yl) benzoic acid; N-ethyl-4- (3- (N-phenylpentaneamido) prop-1-yn-1-yl) benzamide; N- (2- (diethylamino) ethyl) -4- (3- (N-phenylpentaneamido) prop-1-yn-1-yl) benzamide; Ethyl 2- (4- (3- (N-phenylpentanoamido) prop-1-yn-1-yl) benzamido) acetate; 2- (4- (3- (N-phenylpentanoamido) prop-1-yn-1-yl) benzamido) acetic acid; Methyl 2- (4- (3- ( N- phenylpentanoamido) prop-1-yn-1-yl) benzamido) propanoate; 2- (4- (3- ( N- phenylpentaneamido) prop-1-yn-1-yl) benzamido) propionic acid; 2- (4- (3- (N- (3-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid; and 2- (4- (3- ( N- (4-fluorophenyl) pentanoamido) prop-1-ynyl) phenoxy) acetic acid. 3. Una composición farmacéutica adecuada para prevenir o tratar una enfermedad inflamatoria, que comprende: el compuesto de la reivindicación 1 o 2 o una sal farmacéuticamente aceptable del mismo como principio activo.3. A pharmaceutical composition suitable for preventing or treating an inflammatory disease, comprising: the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. Un compuesto de acuerdo con la reivindicación 1 o 2 o una composición farmacéutica de acuerdo con la reivindicación 3 para su uso en la prevención o el tratamiento de una enfermedad inflamatoria, en donde la enfermedad inflamatoria se selecciona del grupo que consiste en asma, ateroesclerosis, cáncer, prurito, artritis reumatoide y enteropatía inflamatoria. 4. A compound according to claim 1 or 2 or a pharmaceutical composition according to claim 3 for use in the prevention or treatment of an inflammatory disease, wherein the inflammatory disease is selected from the group consisting of asthma, atherosclerosis, cancer, pruritus, rheumatoid arthritis, and inflammatory enteropathy.
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